Research Awards Nationwide
This year’s Research Awards Nationwide is searchable. Please use the dropdown boxes to search by topic, state, or grant. If no topic or state is selected, all the information for that area will be displayed.
Additional information is available in the Glossary and Archive. Download the report here.
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Philip Arlen, PhD
MD Anderson Cancer Center Orlando, Orlando, FL
Clinical Patient Care Research GrantFinding The First Signs of Lung Cancer in the Blood
CT scans and molecular markers can help detect cancer at earlier stages, but these tests are not always precise. The researchers will investigate whether a simple blood test can be used to detect lung cancer. The test, called the Cancer Recognition (CARE), measures an antibody that is produced in response to a protein made by cancer cells. Preliminary results have shown that high levels of the antibody are correlated with the presence of lung cancer. The researchers will further evaluate the effectiveness of the test using blood from diagnosed lung cancer patients before and after treatment. They hope to develop a comprehensive detection test that harnesses the power of the immune system, taking advantage of the body’s natural ability to sense the changes the lungs undergo as they become cancerous.
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Asthma Clinical Research Centers
Co-Funded by the Alpha-1 Foundation and MerckEffectiveness of Low-Dose Theophylline As Add-On Therapy In Treatment of Asthma (LODO)
Results: Neither montelukast nor low-dose theophylline improved clinical asthma control, although they both improved lung function equally. Inexpensive low-dose theophylline was more beneficial than montelukast in those patients who had not been prescribed inhaled corticosteroids.
[The American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. American Journal of Respiratory Critical Care Medicine 2007;175:235-42.] -
Asthma Clinical Research Centers
Effect of Positive Airway Pressure on Reducing Airway Reactivity in Patients with Asthma (CPAP)
Co-Funded by the National Institutes of Health’s National Heart, Lung and Blood Institute“The CPAP trial is a prime example of translational research. This study will be a new way to treat asthma without medications.”The development of alternative methods to drug use in improving asthma control is necessary. This study will test whether the use of CPAP, a current treatment for sleep apnea will improve asthma control. CPAP is a way of rthymically increasing airway pressure by applying external pressure through the nose or mouth to prevent large airway collapse during sleep. The researchers propose that applying the same rthymic pressure to the smaller airways will lessen the airway constriction that occurs during an asthma attack. The results of this study may lead to prescribing CPAP to patients with difficulties in achieving asthma control. This proof-of-principle clinical trial will randomize 192 participants, with stable documented asthma and who do not have sleep disorders, into one of three treatment groups for 12 weeks. Treatment arms include: nocturnal CPAP 10 cm H2O, nocturnal CPAP 5 cm H2O and nocturnal sham CPAP.
- Mike Busk, MD, formerly of Indiana University, CPAP Lead-PI -
Asthma Clinical Research Centers
Long-acting Beta Agonist Step Down Study (LASST)
Co-funded by GlaxoSmithKline.“One of the most common dilemmas currently faced by practicing physicians is how to reduce therapy once asthma is controlled on combination ICS/LABA. A study evaluating outcomes of reducing treatment with long term followup and using outcomes relevant to patients and clinicians is needed.”Current asthma guidelines recommend stepping down therapy once asthma is controlled for at least 3 months. For patients treated with inhaled corticosteroids (ICS) alone, a dose reduction of 25-50% to a minimal dose that controls disease is established. However, the optimal approach to reducing treatment in patients with asthma that is well controlled on fixed dose combination ICS/LABA are not clear. The study will compare three approaches of care to patients with asthma well-controlled for three months on combination ICS/LABA therapy: reduction of ICS dose and maintenance of LABA, initial discontinuation of LABA with continuation of ICS, and continuation of stable dose ICS/LABA. The data will allow the determination of the optimal treatment strategy defined as that which results in the lowest rate of treatment failure over 48 weeks of follow- up. Additional exploratory analyses will include assessing risk factors for step-down failure and assessing the optimal duration of time that asthma control should be maintained before therapy is reduced.
- Linda Rogers, MD, New York University, LASST Lead PI -
Asthma Clinical Research Centers
Methacholine Challenge Study (MECIS)Results: The utility of the Methacholine Challenge Test to rule out a diagnosis of asthma depends on racial and atopic characteristics. Clinicians should take into account the reduced sensitivity of the MCT in white and nonatopic asthmatic patients when using this test for the diagnosis of asthma.
[Sumino K, Sugar E, Irvin CG, Kaminsky DA, Shade D, Wei CY, Holbrook JT, Wise RA, Castrio M for the American Lung Association Asthma Clinical Research Centers. Methacholine challenge test: Diagnostic characteristics in asthmatic patients receiving controller medications. Journal of Allergy and Clinical Immunology 2012; 130:69-75.]] -
Asthma Clinical Research Centers
Co-Funded by Schering PloughSinusitis and Rhinitis in Asthma (SIRNA)
Results: A simple, five-item questionnaire, based on the frequency of nasal symptoms, was designed to screen for sinonasal disease and proved more sensitive and specific than sinus CT scans and nasal endoscopy.
[Dixon A, Sugar E, Zinreich J, Slavin R, Corren J, Naclerio R, Ishii M, Cohen R, Brown E, Wise R, Irvin C for the American Lung Association Asthma Clinical Research Centers. Criteria to screen for chronic sinonasal disease. CHEST. 2009;136:1324-1332.] -
Asthma Clinical Research Centers
Smoking Asthmatics Pilot Study (SAPS)
Co-Funded by the National Institutes of Health’s National Heart, Lung and Blood Institute“The treatment of asthma in patients who smokers is an understudied area. It is hoped that our study will lead to improved asthma care for smokers”.About 20% of all people with asthma smoke. Smokers are consistently excluded from therapeutic trials for asthma. As a result current asthma treatment guidelines may not be appropriate for smokers. Indeed, there is good evidence that inhaled corticosteroids, the mainstay for treating persistent asthma, are less effective in smokers. The SAPS trial is designed to test the feasibility of a large scale clinical trial looking at the four main therapeutic options for asthmatic patients who still smoke and are not well controlled on standard asthma therapy. Smoking cessation remains the primary strategy for treating these patients but this study represents an important step in improving care for that significant population of individuals with asthma for whom smoking cessation remains a struggle.
- Joe Ramsdell, MD, University of California, San Diego SAPS Lead PI -
Asthma Clinical Research Centers
Co-Funded by the National Institutes of Health’s National Heart, Lung and Blood InstituteStudy of Acid Reflux in Adults with Asthma (SARA)
Results: The longstanding practice of prescribing heartburn medication is ineffective and unnecessarily expensive for asthma patients who do not exhibit symptoms associated with acid reflux.
[The American Lung Association Asthma Clinical Research Centers. Efficacy of Esomeprazole for treatment of poorly controlled asthma. New England Journal of Medicine 2009;360:1487 -1499.] -
Asthma Clinical Research Centers
Co-Funded by the National Institutes of Health’s National Heart, Lung and Blood InstituteStudy of Acid Reflux in Children with Asthma (SARCA)
Results: The longstanding practice of prescribing heartburn medication is ineffective and unnecessarily expensive for children with asthma who do not exhibit symptoms associated with acid reflux.
[The American Lung Association Asthma Clinical Research Centers. Lansoprazole for Children with Poorly Controlled Asthma. Journal of the American Medical Association 2012; 307(4):373-381.] -
Asthma Clinical Research Centers
Study of Asthma and Nasal Steroids (STAN)
Co-Funded by the National Institutes of Health’s National Heart, Lung and Blood Institute“This research is important because it will allow us to determine if treating sinonasal disease in patients with asthma also affects their asthma management.”Rhinitis and sinusitis are significant causes of morbidity, associated with poor asthma control and increased health care utilization. While the coexistence of asthma and sino nasal disease is well recognized, the interaction between the two processes is not well understood. In previously conducted ACRC trials, researchers have found that over 70% of asthmatics report sinusitis, rhinitis or both. This study will determine if the treatment of chronic sinusitis and rhinitis with nasal steroids improves asthma control, lung function and quality of life in patients with poorly controlled asthma and chronic rhinitis/sinusitis. Four hundred participants aged 12 and over will be randomly assigned to treatment with a nasal steroid or a placebo. The results of this study could provide significant new data to guide therapy in patients with poorly controlled asthma.
- Anne E. Dixon, MD, University of Vermont, STAN Lead PI -
Asthma Clinical Research Centers
Study of Inactivated Influenza Vaccine in Asthmatics (SIIVA) -
Asthma Clinical Research Centers
Co-Funded by GlaxoSmithKlineThe Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol (LOCCS)
Results: Once-daily fluticasone plus salmeterol was as effective as twice-daily fluticasone treatment, while oral montelukast taken once a day was not as effective. However, montelukast did provide control for most patients.
[The American Lung Association Asthma Clinical Research Centers. Randomized Comparison of Strategies for Reducing Treatment in Mild Persistent Asthma. New England Journal of Medicine 2007;356:2027-39.] -
Asthma Clinical Research Centers
Co-Funded by the National Institutes of Health’s National Heart, Lung and Blood InstituteTrial of Asthma Patient Education (TAPE)
Results: Optimistic drug presentation enhances the placebo effect for patient-reported outcomes but not lung function. The effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness.
[Wise RA, Bartlett SJ, Brown ED, Castro M, Cohen R, Holbrook JT, Irvin CG, Rand CS, Sockrider MM, Sugar ES for the American Lung Association Asthma Clinical Research Centers. Randomized trial of the effect of drug presentation on asthma outcomes. Journal of Allergy and Clinical Immunology 2009;124:436-44.] -
Asthma Clinical Research Centers
Use of Mobile Devices and the Internet to Streamline An Asthma Clinical Trial (MICT)
Co-Funded by the National Institutes of Health’s National Heart, Lung and Blood Institute“The treatment of asthma in patients who smokers is an understudied area. It is hoped that our study will lead to improved asthma care for smokers.”Finding participants for research trials is not easy, likely because of the time and effort involved on the participant’s part as well as logistical barriers. The MICT trial will study whether the use of mobile devices and internet technology make clinical trials more convenient and cost effective. Participants in the study will be provided an iPad to take home to complete questionnaires and health information diaries. Rather than coming to the clinic for their appointments, they will utilize FaceTime, a live, video-telephone software application developed by Apple that is built into the device. This will allow them to have real-time interaction with the study staff in the comfort and convenience of their home. Depending on the results of this clinical trial pilot, and, if full-scale clinical trials are conducted, this could potentially change the way that clinical trials are completed in the future, resulting in the potential for even more medical breakthroughs.
- Kathryn Blake, PharmD, Nemours Children’s Clinic MICT Lead PI -
Kameswara Rao Badri, PhD
University of Chicago, IL
American Lung Association Interstitial Lung Disease ScholarSlowing the Development of Pulmonary Fibrosis
Pulmonary fibrosis (IPF) is a disease marked by scarring of the tissue inside and between the air sacs in the lungs causing irreversible damage. As pulmonary fibrosis develops, an increasing number of connective tissue cells called fibroblasts and myofibroblasts accumulate in the lung producing excessive scarring. These cells are activated by a protein called TGF-ß, which plays a central role in these cellular events and represents the most powerful fibrosis-promoting growth factor identified so far. Dr. Badri is investigating the role of P311, a molecule that regulates TGF-ß expression to determine whether a lack of P311 in mice will protect against the development of the disease. He will induce IPF in the mice using a drug called bleomycin. The ultimate goal is to reduce the number of fibroblasts and myofibroblasts through the regulation of different molecular mechanisms associated with the development of IPF.
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Barbara Balestrieri, MD
Brigham and Women’s Hospital, Boston, MA
American Lung Association/American Academy of Allergy, Asthma & Immunology Allergic Respiratory Disease AwardEnzyme’s Role in Lung Inflammation and Asthma
Dr. Balestrieri has found that an enzyme called Group V secretory phospholipase A2 (sPLA2) plays a key role in a mouse model of allergic pulmonary inflammation that has many features of human asthma. sPLA2 has critical functions in the body’s immune response against foreign invaders and its level is increased by exposure to the house dust mite. She has also found that mice genetically modified to lack sPLA2 do not develop a type of macrophage in the lung after they are exposed to dust mites, a common allergen. Dr. Balestrieri hopes to understand how sPLA2 controls the development of macrophages. Once studied in mice, Dr. Balestrieri will continue her research in specimens of severe asthmatic patients. This research could deepen the understanding of how lung inflammation develops, and may lead to a potential therapeutic target for allergic and inflammatory disease.
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Mallar Bhattacharya, MD
University of California, San Francisco, San Francisco, CA
Biomedical Research GrantBlunting Airway Constriction in Asthma
Current therapies for asthma are effective in many circumstances, but the number of patients who die from asthma attacks remains unacceptably high. In an asthma attack, the airways of the lung constrict because of the contraction of a type of muscle known as smooth muscle. Using a mouse model of human asthma, Dr. Bhattacharya will study airway hyper responsiveness, or oversensitivity. He has identified a protein that appears to blunt the constrictive response of smooth muscle when it is triggered by a substance called acetylcholine. He hopes to uncover the way in which this protein, IQGAP1, relaxes smooth muscle contraction. By broadening the understanding of smooth muscle contraction, Dr. Bhattacharya hopes to identify new pathways that could lead to novel treatments for airway constriction in asthma.
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Rudra Bhowmick, PhD
University Of Massachusetts, Worcester, MA
Senior Research Training FellowshipStopping Bacteria from Invading the Bloodstream During Lung Infection
Cells that line the lung, called epithelial cells, usually provide an important barrier to microbial invasion, but S. pneumoniae is somehow able to cross this cell barrier to cause a life-threatening bloodstream infection. Dr. Bhowmick hypothesizes that the outpouring of defense cells called polymorphonuclear leukocytes (PMNs) into the lung, in response to the bacterial infection may itself disrupt the cell barrier, allowing S. pneumoniae to penetrate it and gain access to the bloodstream. To better understand this bloodstream invasion, Dr. Bhowmick will use a mouse model to test drugs for the ability to block the outpouring of PMNs and the movement of S. pneumoniae across the cell barrier, thus protecting the mice from otherwise lethal lung infection. These studies may lead to new ways to prevent serious blood infections following S. pneumoniae lung infection in humans.
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Konstantin Birukov, MD, PhD
University of Chicago
Career Investigator Award 2007-2009Can a Drug Used to Protect Against Radiation Damage Also Treat Lung Injury?
Acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS) are types of severe, acute lung dysfunction affecting all or most of both lungs that occurs as a result of illness or injury. ARDS has a death rate of 30-40%. Despite recent progress in treatment of acute lung injury, there is still no successful strategy to reduce lung damage and tissue injury in this condition.
Dr. Birukov studied the compound amifostine, a drug used to control some side effects of chemotherapy and radiation therapy, to see whether it could significantly reduce acute lung injury induced by infectious agents. Amifostine belongs to a group of drugs called cytoprotectants, which protect normal tissue from some of the side effects caused by some treatments for cancer.
His research, supported by an American Lung Association Career Investigator Award, demonstrated a protective effect of amifostine on acute lung injury induced by infectious agents. In addition to immediate beneficial effects on disease processes triggered by bacteria in the lung, he also discovered that preventive treatment with much lower doses of amifostine stimulates the body’s own antioxidant defense mechanisms and increases resistance to ventilator induced lung injury (VILI). He discovered the mechanisms underlying amifostine’s protective effects, which may be used to develop novel clinical therapies for the treatment of ALI and VILI.
“American Lung Association awards granted to me and two other recipients, Patrick Singleton and Anna Birukova, allowed us to enhance and extend our research programs, and our interactions were a key element in organizing the Lung Injury Center with the valuable support of the Pulmonary Section and The University of Chicago Department of Medicine,” he says. “Our Center’s major mission is lung research and training the next generation of young scientists.”Publications:
Fu P, Birukova AA, Sammani S, Burdette DO, Murley JS, Garcia JGN, Grdina DJ, Birukov KG. The protective role of amifostine in preventing LPS-induced acute lung injury. Resp. Crit. Care Med. 175:A783, 2007.
Birukova AA, Cokic I, Moldobaeva N, Birukov KG. Amifostine reduces lypopolysacharide-induced lung dysfunction via suppression of redoxsensitive inflammatory signaling. Proceedings of the European Respiratory Society; October 2008
Fu P, Birukova AA, Xing J, Sammani S, Murley JS, Garcia JG, Grdina DJ, Birukov KG. Amifostine reduces lung vascular permeability via suppression of inflammatory signaling. Eur Respir J. 2009; 33(3):612-24.
Birukov KG. Cyclic stretch, reactive oxygen species and vascular remodeling. Antioxidants & Redox Signaling, 2009; 11(7): 1651-1667.
Fu P, Murley JS, Grdina DJ, Birukova AA, Birukov KG. Induction of cellular antioxidant defense by amifostine improves ventilator-induced lung injury. Crit Care Med, 2011 Dec;39(12):2711-21.
Birukov KG. “Ventilator induced mechanical stress and lung vascular dysfunction”. In: Textbook on Vascular Disease; J. X. – J. Yan et al. (eds.). Springer Science., DOI 10.1007/978-0-387-87429-6_64, 2011 -
Trever Bivona, MD, PhD
University of California, San Francisco, San Francisco, CA
Lung Cancer Discovery AwardImproving Personalized Treatment for Lung Cancer
“This is a watershed moment in the history of cancer treatment research,” says Trever Bivona, MD, PhD, recipient of this year’s American Lung Association Lung Cancer Discovery Award. A growing number of lung cancer patients are being treated with drugs that target the genetic cause of their lung cancer, known as personalized medicine. Yet while patients may respond quickly, they often become resistant to the treatment.
“This is a watershed moment in the history of cancer treatment research.”Dr. Bivona’s research focuses on lung cancers that are associated with a particular mutation in a gene called EGFR. Patients with this type of lung cancer are treated with a drug called erlotinib (Tarceva), which blocks the mutant form of EGFR. While the treatment induces tumor regression, the cancers develop resistance to the drug. Dr. Bivona hopes to better understand how lung cancer becomes resistant to erlotinib.
When he analyzed potential genes that might be causing this resistance, using human lung cancer grown in the laboratory and also in mice, he and his team discovered that the most prominent gene involved was one called AXL. This gene is turned on and allows EGFR-mutant lung cancers to survive in the face of erlotinib treatment. He hopes to discover how AXL is turned on in the setting of erlotinib resistance and how AXL promotes erlotinib resistance in lung cancers.
AXL is a type of enzyme called a kinase. “It turns out this class of enzyme is a very good drug target. Kinases can be targeted with potent drugs, and there are a host of therapies that have emerged in the last few years that target kinases, but none of them are highly specific against AXL,” Dr. Bivona says. “Many drug companies have been working on developing new drugs targeting kinases, including AXL. That means we can move rapidly to test drugs that target AXL and potentially use them for clinical testing. This paves the way for very rapid clinical translation.”
He is collaborating with Dr. Kevan Shokat, a Howard Hughes Medical Institute Investigator and chair of the UCSF Department of Cellular and Molecular Pharmacology at the University of California, San Francisco to develop new drugs that target AXL.
“The American Lung Association grant will accelerate this line of investigation,” Dr. Bivona said. “Without this funding, it would be very difficult to go forward with testing drugs and moving the most promising ones toward the clinic. It’s a real catalyst.”
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Emilie Bourdonnay, PhD
University Of Michigan, Ann Arbor, MI
Senior Research Training FellowshipGetting the Lungs to Improve Their Defense against Pneumonia
In the lung, cells called alveolar macrophages (AMs) are strategically located to defend the lung against infectious agents. These cells fight infections by ingesting and killing microbes. During lung infections, the body produces a biochemical messenger called prostaglandin E2 (PGE2) at high levels. Even in the absence of infection, PGE2 is overproduced when the immune system is suppressed in some people, such as those with AIDS. PGE2 suppresses AMs, and inhibits their microbial killing functions. The researchers will study the mechanisms that regulate how AMs kill microbes, and how this AM killing function is impaired by PGE2. The results could lead to novel therapeutic approaches to improve lung immune defenses and to treat pneumonia.
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James Bridges, PhD
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Biomedical Research GrantKnowing Protein’s Role in Airway Remodeling May Lead to New Treatments
Enlargement of the smooth muscle layer surrounding the airways, also known as airway remodeling, is a common feature of many chronic lung diseases including asthma, and chronic obstructive pulmonary disease (COPD). The mechanisms contributing to airway remodeling are poorly understood but the researchers believe a protein called hypoxia inducible factor 2a (HIF2a) may play a role. The researchers will determine the role of HIF2a in airway smooth muscle using mouse models of allergen-induced asthma. They will use mice that have increased or decreased levels of HIF2a in airway smooth muscle cells. The long-term goal of this research is to identify how smooth muscle becomes dysfunctional, and to develop novel treatment targets for chronic airway disease.
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Gang Chen, PhD
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Senior Research Training FellowshipGene May Provide Clue to Mucus Production
The reason the lungs of patients with chronic lung disease such as asthma, cystic fibrosis and chronic obstructive pulmonary disease clog with thick mucus, leading to infection and inflammation, is unclear. There are only a few treatments available to treat this mucus, and they are often not very effective. Dr. Chen will identify the biological function of a gene called FOXA3, which is “quiet” in healthy lungs but heavily increased in lung cells that produce mucus in patients with chronic lung diseases. Preliminary studies demonstrated that FOXA3 has a dual role in the lung’s epithelia, cells that line the airways - controlling mucus production and suppresses lung inflammation. Dr. Chen will identify the momolecular mechanisms of FOXA3 that influence lung epithelial cell function in health and disease. This will help identify new pharmacological targets to treat chronic lung diseases, and will provide new strategies for diagnosis, prevention and treatment of these diseases.
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J. Robert Coleman, PhD
State University of New York, Farmingdale, NY
Biomedical Research GrantNew Streptococcus Pneumonia Vaccine Would Protect Against All Strains
Streptococcus pneumonia (SP) is the leading cause of bacterial pneumonia in the United States and worldwide. There are two current vaccines for SP—one for adults and one for children. However, each are limited as neither vaccine protects against all 92 strains of SP that have emerged and caused disease in susceptible populations. Dr. Coleman hopes to construct a ‘universal’ vaccine capable of protecting against all 92 strains of SP. He will redesign genes that are shared by all strains of SP to produce a weakened strain that over-expresses ‘protective’ proteins. In an initial study that used this approach, Dr. Coleman and his team found the redesigned strain was less virulent and could serve as a prototype vaccine.
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J. Lucian Davis, MD, MAS
University Of California, San Francisco, San Francisco, CA
Clinical Patient Care Research GrantNew DNA Test May Cut Down on Unneeded TB Treatment
Public health interventions such as quarantining patients in the hospital, and interviewing close family, friends and coworkers for evidence of TB usually begin prior to receiving an actual TB diagnosis. This is due to the inadequacies of the existing tests for TB—a sputum test that takes two months to provide final results, and other rapid tests that both under- and over-diagnose TB. As a result, many patients who are suspected of having TB suffer medication side effects and may not be treated for the true cause of their underlying respiratory symptoms. Dr. Davis will determine if a new automated DNA fingerprinting test for TB, GeneXpert provides a rapid, accurate alternative to the existing diagnostic approaches, cutting down on unnecessary treatment and public health interventions among patients who are suspected of having TB.
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Taylor Doherty, MD
University of California, San Diego, San Diego, CA
American Lung Association/American Academy of Allergy, Asthma & Immunology Allergic Respiratory Disease AwardHow Do ‘Natural Helper Cells’ Lead to Asthma After Mold Exposure?
Many people with asthma have worsening inflammation in their lungs after exposure to their allergy triggers. One particular mold allergen, Alternaria, has been associated with severe asthma, including life-threatening attacks. Dr. Doherty has evidence that a recently discovered white blood cell type in the lung, called a natural helper cell, may be very important in establishing lung inflammation and oversensitivity of the airways after exposure to Alternaria. He will test the importance of natural helper cells in an animal model of asthma, and determine ways that the immune system reacts in the lung after exposure to Alternaria. This research will help in the understanding of immune system responses in asthma, and perhaps lead to the discovery of therapeutic targets.
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Jeffrey Engelman, MD, PhD
Massachusetts General Hospital, Boston, MA
Lung Cancer Discovery AwardCan We "Teach" Cancer Cells to Die "On Time"
Targeted therapies are increasingly being used to treat advanced lung cancer. These specialized treatments aim to disrupt specific processes needed for a cancer cell’s growth and survival. Yet, some cancer cells are intrinsically more resistant to targeted therapies. Dr. Engelman will study a protein named BIM, which governs a process called apoptosis, or programmed cell death. Preliminary studies have found that patients whose cancers have low BIM levels received less benefit from the same targeted therapy as patients whose cancers have high levels of BIM. Dr. Engelman has identified new strategies to induce cell death in the cancers lacking BIM. His aim is to determine which patients will derive the greatest benefit from targeted therapies, and to identify alternative treatments that may be more effective for cancers with low BIM and normally have reduced responses to targeted treatments.
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Ming-Hui Fan, MD
University of Pittsburgh, Pittsburgh, PA
Dalsemer Research GrantA Novel Protein May Protect Lungs Against Scarring After Injury
When Ming-Hui Fan, MD, took care of pulmonary patients during her residency, she was especially moved by those suffering from idiopathic pulmonary fibrosis (IPF). “These patients really stuck out in my memory, because we had no way of helping them,” she says. “When I decided to specialize in pulmonary medicine, IPF was a major area of interest for me.”
“These [IPF] patients really stuck out in my memory, because we had no way of helping them.”IPF is characterized by progressive lung injury and scarring, leading eventually to death within two to four years of diagnosis on average unless the patient undergoes a lung transplant. Little is known about the cause of the disease, and no effective medical treatments exist to reverse or even to slow down its progress.
While doing her pulmonary and critical care fellowship at the University of Pennsylvania, she worked with cancer researcher Ellen Puré, PhD, whose lab had discovered that tissues of patients with IPF had increased levels of a protein called fibroblast activation protein (FAP). This protein has the ability to break down scar tissue in the lung. It is produced in the developing embryo and production is turned off shortly after birth. It is not produced in normal healthy adult tissues.
Dr. Fan found mice bred to be deficient in FAP have decreased survival and increased lung scarring. Her work demonstrates that FAP lessens the degree of pulmonary fibrosis that develops after lung injury in mice. “We don’t have a clear picture of what FAP acts on,” she says. She hopes to gain a greater understanding of this in her current research, which seeks to take what she has learned from mice into humans. To do this, she is studying lung fibroblasts (cells which produce the collagen of scar tissue) grown from the lungs of IPF patients who received transplants.
“We have shown that FAP plays a protective role in the lung, minimizing scarring after injury,” Dr. Fan notes. “Now we can consider ways to increase FAP expression, enhance enzymatic activity, and try to find out exactly what FAP is affecting in the tissue in order to boost its effect downstream.”
Her American Lung Association Dalsemer Research Grant has provided her the opportunity of having additional staff support. “I’ve been able to get extra hands to help with the work, which has been enormously helpful,” she says. “I can focus more on the big picture.” -
Yoichi Furuya, PhD
Albany Medical College, Albany, NY
Senior Research Training FellowshipIntranasal Influenza Vaccine’s Effectiveness in Asthmatics
People with asthma not only suffer from constant wheezing and coughing but are also believed to be more prone to serious lung infections such as bronchitis and pneumonia. Various public health organizations strongly recommend that people with asthma receive vaccinations against respiratory pathogens such as the influenza virus. While the flu shot has been shown to be effective in asthmatics, little is known about the effectiveness of the nasal spray influenza vaccines. Dr. Furuya has found that asthmatic mice immunized with the live influenza virus are highly susceptible to influenza virus infections. He will investigate why the nasal spray vaccine, which uses a weakened live flu virus, does not appear to be effective in asthmatics. His hope is to overcome asthmatics’ poor immune response by adding compounds to commercially available influenza vaccines. The findings could lead to development of new vaccines or therapies that will help prevent or treat influenza in people with asthma.
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Ramesh Ganju, PhD
Ohio State University, Columbus, OH
American Lung Association Lung Cancer ScholarCan an Enzyme Really Cause So Much Damage?
About 90 percent of lung cancers are non-small cell lung cancer (NSCLC). Many patients with the disease become resistant to chemotherapy, and fewer than 20 percent live beyond five years after diagnosis. Dr. Ganju will investigate whether an enzyme called fatty acid amid hydrolase (FAAH) can interfere with a natural brain compound that he believes can block the growth and spread of lung cancer. These natural brain compounds, known as endocannabinoids, attaches to receptors called CB1 and CB2. These are found on cells that regulate the progression and spread of NSCLC to other organs and systems. He will test the ability of endocannabinoids to block the growth and spread of cancer and whether this process is stopped by FAAH in mice. The results of this award may lead to future research that could lead to new treatments for NSCLC to help people live longer.
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Aris Garro, MD, MPH
Rhode Island Hospital, Providence, RI
American Lung Association/The CHEST Foundation Asthma Clinical Patient Care GrantWhich Children With Uncontrolled Asthma Need Inhaled Steroids?
Many children with poorly controlled asthma use emergency departments for asthma care, but are infrequently prescribed inhaled steroids at these visits. These visits are an opportunity to improve long-term asthma management. Using a tool called the Pediatric Asthma Control and Communication Instrument (PACCI), Dr. Garro will test if children who receive the PACCI have better asthma control than children who receive routine asthma discharge instructions. Dr. Garro will also interview parents to figure out what determines whether they fill the prescriptions and use the medicine appropriately. Dr. Garro’s research will hopefully determine the best way to assist emergency doctors in deciding which children should be prescribed inhaled steroids at discharge and how they can best educate families to give the appropriate medicines to their children.
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Gregory Mark Gauthier, MD
University of Wisconsin, Madison, WI
Biomedical Research GrantSwitching Between Mold and Yeast to Cause Infection in the Lungs
Worldwide, dimorphic fungi (fungi that have two different forms) are the most common cause of invasive fungal infection, infecting people with both normal and impaired immune systems. These fungi grow as mold in soil and produce infectious particles called spores. When the soil is disrupted (through construction, windstorms or earthquakes, for example), spores enter the air and can be inhaled into the lungs. Once inside humans’ warmer lungs, the spores convert into round, budding yeast to cause pneumonia. Dr. Gauthier will examine how these fungi sense temperature and convert between mold and yeast forms, allowing these organisms to cause human infection. He will attempt to uncover the genes that regulate the switch between mold and yeast in the fungi. The results have the potential to help identify novel antifungal drug targets and drugs which are desperately needed.
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Elena Goncharova, PhD
University of Pennsylvania,Philadelphia, PA
Biomedical Research GrantStopping the Growth of Smooth Muscle in the Lungs
A life-threatening complication of Lymphangioleiomyomatosis (LAM) is pulmonary arterial hypertension (PAH), which also affects people with other lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis. In PAH, the pulmonary arteries constrict abnormally, which allows less blood to circulate through the lungs to pick up oxygen. For unknown reasons, exposure to chronic lack of oxygen, called hypoxia, triggers the growth of smooth muscle in the walls of pulmonary arteries leading to a thickening of artery walls, high blood pressure and heart failure. Dr. Goncharova’s research is focused on a protein called mammalian target of rapamycin (mTOR), which has been shown to regulate cell growth and proliferation. Dr. Goncharova is investigating what activates mTOR and how mTOR acts to promote vascular smooth muscle cell growth with the hope that it could lead to development of new therapies to inhibit smooth muscle cell growth in pulmonary arteries in PAH.
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Sergei Grando, MD, PhD, DSCI
University of California, Irvine, CA
Lung Cancer Discovery AwardInterfering in Tobacco’s Cancer-Causing Effect on Lung Cells
Identifying the mechanisms by which tobacco leads to the cancerous transformation of lung cells may prove useful in preventing lung cancer. Dr. Grando will investigate nicotine-induced changes of binding of a hormone-like molecule called acetylcholine to its receptors on lung cells, called nicotinic acetylcholine receptors (nAChRs). Dr. Grando will determine if specific drugs that can block the ability of cancer-causing tobacco byproducts called nitrosamines to bind to lung nAChRs can also decrease their cancer-causing effect on lung cancer and lung tumor development in mice. The results of this research will contribute to a better understanding of the way in which tobacco leads to cancer, and open a door for new approaches to treatments that will interfere in this process.
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Alyssa Gregory, PhD
University Of Pittsburgh, Pittsburgh, PA
Senior Research Training FellowshipEnzyme’s Clues to Lung Changes in Idiopathic Pulmonary Fibrosis
Effective treatments for idiopathic pulmonary fibrosis (IPF), a severe lung disease in which patients develop shortness of breath, decreased exercise capacity, lung scarring (fibrosis) and difficulty with oxygen exchange, do not currently exist. Dr. Gregory will study an enzyme called neutrophil elastase, which is found in high levels in IPF patients. Preliminary evidence suggests that this enzyme may play a key role in the development of IPF. She will examine whether this enzyme can gain entry into cells called fibroblasts that are found in connective tissue, and cause key changes in cellular behavior, which negatively affect IPF patients. Her hope is to define the way in which neutrophil elastase contributes to IPF, leading to an important new target for IPF therapy.
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Christoph Grundner, PhD
Seattle Biomedical Research Institute, Seattle, WA
Biomedical Research GrantStopping the TB Germ before It Causes Trouble
Multiple drug-resistant (MDRTB) and extensively drug-resistant (XDR-TB) strains of Mycobacterium tuberculosis (Mtb) are virtually resistant to every drug currently available. In countries with poor TB control programs, MDR-TB can account for over a quarter of all new TB cases and many high-burden countries do not even test for XDR-TB due to lack of resources. Targeting Mtb while it is latent, before it causes active disease, is exceedingly difficult, and new drug targets are urgently needed. Dr. Grundner will explore the function of two Mtb enzymes that may offer novel drug targets for treating Mtb. By knocking out these enzymes genetically and with chemical inhibitors, he hopes to define the role of these enzymes in a model of Mtb growth, latency, reactivation and replication.
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Finn Hawkins, MB, BCh, BAO
Boston University, Boston, MA
Senior Research Training FellowshipWorking Toward Regenerating Damaged Lung Tissue
For many Americans living with end-stage lung disease such as pulmonary fibrosis and cystic fibrosis, lung transplant is the only option. Even if patients are fortunate enough to receive one of the relatively scarce donor lungs for transplant, their life expectancy is worse than for other types of transplants due to complications such as organ rejection and infections. An ideal alternative would be to repair or regenerate damaged lungs. In 2006, scientists in Japan made a significant breakthrough when they discovered induced pluripotent stem cells (iPS)—adult cells that have been genetically reprogrammed into a cell that has the ability to turn into any cell type in the body. Dr. Hawkins’ goal is to develop the technologies to generate a transplantable, functioning lung from iPS cells. He also plans to test whether “corrected” iPs cells, which previously had the mutation that caused cystic fibrosis, can function normally. These advances would represent critical breakthroughs toward the goal of treating lung disease.
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Deborah Weide Hendricks, PhD
University of California, San Francisco, San Francisco, CA
Senior Research Training FellowshipLearning How Immune Cells Fight Respiratory Infections
When a cell is infected with a virus, natural killer cells (NK) respond rapidly, producing proteins that kill the cell directly or that helps other immune cells fight the virus. Recent studies have indicated that NK cells recognize certain viruses, and that they may “remember” their first encounter with a virus and provide better protection during the next infection. These qualities make vaccinations possible. Dr. Hendricks will study the function and characteristics of these NK cells during parainfluenza virus infection, a highly transmissible respiratory infection that is responsible for widespread illness especially among children, older adults and those with suppressed immune systems. Ultimately, Dr. Hendricks hopes to translate the knowledge she gains from this research into better treatments for respiratory infections.
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Caroline Herndon, PhD
The CBR Institute for Biomedical Research, Boston, MA
Senior Research Training FellowshipInsights Into the Body’s Immune Response to Influenza
Although vaccination against influenza usually causes a protective antibody response, the ability of the virus to mutate allows new strains to invade the immune system and cause infection. Studies in mice have shown that the abil-ity of respiratory dendritic cells (RDCs) to bind influenza in the lungs and transport it to the lungdraining lymph node (LN) is critical for the start of the body’s immune response to influenza. The way in which RDCs bind and transport influenza is largely unknown, as is the fate of the RDCs when they arrive in the LN. Dr. Herndon will investigate these mechanisms, focusing on the complement system, which is a series of proteins that circulate in the blood and become activated in response to bacteria and viruses, triggering inflammation and alerting white blood cells to the presence of foreign invaders. This information could help inform better intervention strategies against influenza and other respiratory pathogens, such as dendritic celltargeted vaccines.
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Kevin Hill, MD, MHS
McLean Hospital, Belmont, MA
Clinical Patient Care Research GrantTB Drug Could Aid Smoking Cessation
Kevin Hill, MD, MHS is investigating whether an antibiotic already approved by the U.S. Food and Drug Administration for the treatment of tuberculosis will help people quit smoking. Preliminary evidence suggests that the drug, D-cycloserine (DCS), may be able to help smokers make better use of their counseling sessions by enhancing their ability to learn how to avoid smoking.
“If we find this drug is effective in helping people to quit smoking, the translation into practice would be relatively quick, since this is a drug that is already readily available.”There is a great need for more effective treatments for smoking cessation, Dr. Hill says. “Success rates for currently available treatments are, at best, around 35 percent at six months.” he notes. “If we could take the best available treatments, such as nicotine replacement therapy (NRT) and cognitive behavioral therapy (CBT), and magnify their effects, it would have a tremendous impact upon millions of smokers who want to quit. If we could boost success rates by an additional 15 percent, for example, that would mean half of smokers would experience some type of success in quitting smoking, and then we’d have a lot more people willing to get into treatment.”
CBT is a type of talk therapy that is used to treat nicotine dependence, as well as a number of other conditions including panic disorder and general anxiety disorder. In CBT for smoking, patients work with their therapist on how to handle high-risk smoking situations so that gradually they will become desensitized to the feelings of craving that occur whenever they are exposed to smoking cues. DCS enhances this process, called extinction learning, by working on receptors in the brain called NMDA receptors, which are associated with learning. “DCS works on these receptors by dampening the reaction, making you more likely to be able to dissociate a cue, such as seeing a cigarette, with a response of wanting to smoke,” Dr. Hill says.
He is thrilled to have received an American Lung Association grant. “We’ve been trying to secure funding for this research for several years, and now that we have it, we are pushing full speed ahead with the study. If we find this drug is effective in helping people to quit smoking, the translation into practice would be relatively quick, since this is a drug that is already readily available.”
Dr. Hill will also study the effects of DCS on learning and memory, through neuropsychological tests. “If the drug is enhancing the extinction learning process, we can use neuropsychological testing to see why it is working,” he says. “That information may help us determine if particular patients are more responsive than others to this treatment.” -
Kelly Hume, DVM
Cornell University, Ithaca, NY
Biomedical Research GrantImproving Lung Cancer’s Responsiveness to Chemotherapy
Using molecular genetics, Dr. Hume intends to study a novel therapeutic strategy called checkpoint protein impairment, which holds great promise in sensitizing lung cancers to be more responsive to chemotherapy. In cells, certain checkpoints, or control mechanisms, function to protect DNA from damage. She will impair the checkpoint protein Hus1 to see if this stops the progression of lung cancer and if it allows cancer cells to become more sensitized to the chemotherapy drug cisplatin. The findings of this study may be used to develop drugs that target checkpoints involved in lung cancer, which would work in synergy with chemotherapy to improve remission rates for patients with advanced lung cancer.
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Landon Inge, PhD
St. Joseph’s Hospital & Medical Center, Phoenix, AZ
Biomedical Research GrantDrug Could Help Some Patients With Non-Small Cell Lung Cancer
Non-small cell lung cancer (NSCLC) is a deadly disease, yet minimal advances have been made in its treatment. Recent evidence indicates that gene alterations that inactivate a protein called LKB1 play a critical role in the growth and spread of up to half of NSCLC tumors. Targeting LKB1 alterations will help a large portion of patients. In previous studies, Dr. Inge and his team found that exposing NSCLC cells lacking LKB1 to a compound called 2-D-deoxyglucose can cause death in those cells. Dr. Inge will study 2-D-deoxyglucose in an animal model of lung cancer lacking LKB1. He hopes his work will lead to use of this compound to treat NSCLC in humans.
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Jean-Francois Jasmin, PhD
Thomas Jefferson University
Biomedical Research Grant 2009-2011Can Membrane Protein Prevent Development of Pulmonary Hypertension?
Pulmonary arterial hypertension (PAH) is a disease of high blood pressure in the arteries of the lungs. PAH is progressive and lifethreatening because the pressure in a patient’s pulmonary arteries rises to dangerously high levels, putting a strain on the heart. None of the current drugs cure or halt the progression of this disease.
Publications:Caveolin-1, or Cav-1, is a membrane protein that has recently been shown to be involved in the regulation of pulmonary arterial hypertension. Decreases in Caveolin-1 expression have been reported in patients with severe pulmonary arterial hypertension.
de Almeida CJ, Witkiewicz AK, Jasmin JF, Tanowitz HB, Sotgia F, Frank PG, Lisanti MP. Caveolin-2-deficient mice show increased sensitivity to endotoxemia. Cell Cycle. 2011 Jul 1;10(13):2151-61.
Jasmin JF, Rengo G, Lymperopoulos A, Gupta R, Eaton GJ, Quann K, Gonzales DM, Mercier I, Koch WJ, Lisanti MP. Caveolin-1 deficiency exacerbates cardiac dysfunction and reduces survival in mice with myocardial infarction. Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1274-81.
Dr. Jasmin used an American Lung Association Biomedical Research Grant to study whether a Caveolin- 1-mimetic peptide can reverse the development of pulmonary arterial hypertension in an animal model. He treated hypertensive rodents at various stages of the disease with a Cav-1-mimetic peptide to see at which point the treatment might decrease pressure in the arteries and improve survival.
He found that administering Cav-1 not only reduced the development of PAH and the enlarged right heart ventricle that accompanies it, but also improved survival in rats. “The results could have a direct impact on the management of human PAH”, Dr. Jasmin says.
He plans to continue investigating the mechanisms underlying the development of pulmonary hypertension. “This Biomedical Research Grant definitely jump-started my pulmonary hypertension research program and I am thankful to the American Lung Association for this opportunity,” he added. -
Pushpa Jayaraman, PhD
Brigham & Women’s Hospital
Senior Research Training Fellowship 2009-2011Learning How the Immune System Defends Itself Against TB Bacteria
Mycobacterium tuberculosis, which causes pulmonary tuberculosis, is able to establish chronic infection in humans and evade the body’s immune system defenses. Pushpa Jayaraman, PhD, used an American Lung Association Senior Research Training Fellowship to study a novel mechanism to kill M. tuberculosis. Dr. Jayaraman, who is from India, is particularly interested in TB, because she has seen the high toll the disease has taken in her country.
Publications:Her research is centered on immune system cells called macrophages that are the first line of defense against airborne pathogens. They engulf M. tuberculosis, bringing it to white blood cells called T cells, which should kill the TB germ. However, M. tuberculosis is able to take refuge in macrophages by diverting some host defense mechanisms. This hijacking of the macrophage defense system interferes with the ability of the immune system to protect people from disease.
Jayaraman, P, Sada-Ovalle, I, Beladi, S., Anderson AC, Dardalhon V, Hotta C, Kuchroo VK, Behar SM. Tim3 binding to galectin-9 stimulates antimicrobial immunity. J Exp Med 2010. 207 (11) 2343-2354.
Sakuishi K, Jayaraman P, Behar SM, Anderson AC, Kuchroo VK. Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 2001. 32(8): 345-9.
She focused on recently discovered molecules called Tim3 on the surface of T cells, and how they regulate the macrophage response to M. tuberculosis. Tim3 expression levels on T cells increase following M. tuberculosis infection. She found that mice infected with TB who were treated with the Tim3 protein experienced a dramatic reduction in the TB bacteria in their lungs. Dr. Jayaraman’s American Lung Association grant allowed her to discover the signaling pathways activated by Tim3 in M. tuberculosis-infected macrophages. She studied a novel way in which Tim3 on T cells can activate M. tuberculosis-infected macrophages by binding to its receptor, Galectin-9 (Gal9) on M. tuberculosis-infected macrophages. Gal9 sends a signal into the macrophage and activates it through the secretion of antimicrobial immune system cells called cytokines, such as IL-1b and TNF, arming the macrophages to efficiently kill M. tuberculosis.
Her research demonstrated a new biological function of Tim3, discovering how it stimulates immunity against microbes. Based on her findings, she concludes that Tim3 and Gal9 represent novel cell targets that could be used to develop new medications to activate macrophages to fight TB.
Dr. Jayaraman’s American Lung Association grant led to further grants to study Tim3 and tuberculosis, from the National Institutes of Health and the Harvard University Center for AIDS Research. -
Faye Johnson, MD, PhD
University of Texas M.D. Anderson Cancer Center, Houston, TX
Lung Cancer Discovery AwardDrug May Inactivate Pathway That Promotes Lung Cancer
One way to identify new genetic changes that may predict responses to personalized anti-cancer therapy is to analyze patients who respond well to such agents. A patient with non-small cell lung cancer (NSCLC) treated with a drug called dasatinib had a partial response that continued to evolve over time, and he remains free of active cancer over four years later, without further treatment. The patient has a novel mutation in a protein called BRAF that is important for cancer progression. The mutation results in substantial impairment of BRAF’s enzyme activity. Dr. Johnson will study the mechanism by which inactive BRAF makes NSCLC cells sensitive to dasatinib. She will also study the effectiveness of dasatinib against NSCLC in patients whose tumors have mutations that inactivate BRAF. The results could lead to substantial benefits to thousands of patients with this deadly disease.
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Sun Kim, PhD
University of Massachusetts
Social Behavioral Research Grant 2008-2010Finding Effective Ways to Get Korean Americans to Quit Smoking
Korean male immigrants in the United States have the highest rate of current smoking and the highest rate of cancer deaths caused by smoking among subgroups of the Asian American population. However, this is also one of the groups studied least in regards to smoking and smoking cessation. Many Asian Americans, including Korean Americans, tend not to seek treatment for smoking cessation that is available in public healthcare settings due to language and cultural differences. In addition, Korean Americans have been identified as the group with the highest uninsured rate of all racial and ethnic groups, including Hispanics.
Publications:In an effort to prevent lung diseases caused by smoking, Dr. Kim sought to identify psychological, social, cultural, and behavioral factors that may predict Korean Americans’ willingness to quit smoking and to seek cessation treatment. She also wanted to explore their experiences with the treatment, particularly regarding actual and perceived difficulties accessing the treatment. Dr. Kim interviewed 168 Korean males and 94 Korean females who had smoked daily for the previous six months. Those who were interested in quitting received smoking cessation counseling. The study helped Dr. Kim to understand how Korean women differ from Korean men in smoking and quitting behaviors, which warrants the development and implementation of gender-specific smoking cessation interventions. She developed a proposal for a smoking cessation program delivered via webcam, which provides privacy in a community with a strong social taboo against women smokers. Dr. Kim notes that many Asian female smokers refuse to seek help because they fear others will find out they smoke. She hopes to find funding for her new study, which will also include other Asian American female populations.
Kim SS, Fang H, DiFranza J, Ziedonis D, Ma G. (in press). Gender differences in the Fagerstrom Test for Nicotine Dependence in Korean Americans. Journal of Smoking Cessation.
Dr. Kim has received a National Institutes of Health/ National Institute on Drug Abuse grant to study tobacco dependence treatment for Asian Americans. -
Shyny Koshy, PhD
Baylor College Of Medicine, Houston, TX
Senior Research Training FellowshipTargeting Potassium Channels May Lead to Asthma Treatment
White blood cells called T cells produce inflammatory proteins, and are major contributors to the development of asthma. These T cells have channels on their surface that allows potassium ions to enter and exit the cells. This ion exchange is essential for normal functioning of the T cell. Blocking the potassium channel on these cells will cause them to become inactive, and thus reduce the severity of asthma. The researchers will first determine whether blocking specific potassium channels affects the functions of the T cells from patients with asthma. They will then use a drug that blocks potassium channels to treat asthma in a rat model of chronic asthma. The findings of this study may point to new therapeutic targets for chronic asthma.
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Gee Lau, PhD
University Of Illinois At Urbana-Champaign, Champaign, IL
Desouza Research AwardToxin Could Provide Clues to Bronchiectasis Treatment
Bronchiectasis is a chronic inflammatory condition that causes airways to widen, weaken and lose elasticity. It is an important component of cystic fibrosis. There is no cure for bronchiectasis, but proper control of infection and other treatments can improve the quality of life for patients. The researchers will examine the disease-causing ability of a toxin called pyocyanin that is produced by the bacteria Pseudomonas aeruginosa, which often grows in mucus of bronchiectasis-affected airways. This toxin causes exaggerated inflammatory response and worsens mucus overproduction. They will study how pyocyanin causes excess mucus production. The results will be useful in developing novel and effective anti-infective therapies to reduce illness and death in patients with this disease.
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Youngnam Lee, PhD
University of California, San Francisco, CA
Senior Research Training FellowshipLearning More about an Understudied Fungus
Histoplasma capsulatum is a fungus found in the soil, especially in the Ohio and Mississippi River Valley regions in the Midwest and Central and South America. When the soil is disturbed, parts of the fungus can be inhaled, entering the lungs and infecting lung immune cells called alveolar macrophages (AM). This inhalation can cause a disease called histoplasmosis in people who have compromised immune systems, such as those with AIDS, or undergoing transplantation or chemotherapy. When H. capsulatum infects AM, it divides within the cell and eventually kills the cell. This may lead to the spread of the fungus to new cells and organs if left unchecked. Dr. Lee is studying a mutated version of H. capsulatum that can grow within the body’s cells, but cannot kill the cells. This H. capsulatum mutant lacks a protein called Cbp1 and the researcher’s hope to find other proteins or factors with which Cbp1 interacts to induce this killing.
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Ian Lewkowich, PhD
Children’s Hospital Medical Center
Senior Research Training Fellowship 2006-2008Why Do Regulatory T Cells Not Work in People with Allergic Asthma?
A complex immune response is involved in asthma, and much is still not understood about this process. Dr. Lewkowich has focused his research on the role a specific cell, a “regulatory” T cell, or TReg, plays in preventing allergic asthma.
TRegs normally help control immune system responses before they become damaging. Tregs inhibit immune responses by acting on two main targets. By targeting other T cells, Tregs can inhibit existing immune responses, while targeting a second cell type, the dendritic cell, prevents the development of immune responses. Dr. Lewkowich found that mice that are susceptible to the development of an experimental form of asthma have many TRegs, but these TRegs do not function like those in mice without asthma.
Through an American Lung Association Senior Research Training Fellowship, Dr. Lewkowich hoped to find out whether the mice with asthma are not producing some substance needed to turn off the responses that cause asthma; whether the TRegs in asthmatic mice are normal, but other cells simply fail to see them, or a combination of the two.
He studied mice that were susceptible to asthma and those that were resistant to asthma, and found although exposure to allergens increased the production of certain substances by Tregs, there were no differences between the two sets of mice. However, when the ability of Tregs to act on another cell involved in the immune response, dendritic cells, was measured, Tregs (whether they came from asthma-susceptible, or asthma-resistant mice) successfully targeted dendritic cells from resistant mice, but not those from susceptible mice. This demonstrates that the defect lay in the ability of dendritic cells to respond to Tregs, not in the Tregs themselves. Further experimentation has revealed that a particular inhibitory pathway crucial for the ability of Tregs to target dendritic cells appears to be non-functional in the mice susceptible to asthma.
Experiments are currently underway to overcome this defect in asthma-susceptible mice, increasing their resistance to the development of allergic asthma.Publications:
Lewkowich, IP et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. (202): 1549-1561, 2005.
Kohl, J., Baelder, R., Lewkowich, IP. et al. A regulatory role for the C5a anaphylotoxin on type 2 immunity in asthma. J. Clin. Invest. (116): 783-796, 2006.
Rothenberg, MR., Doepker, MP, Lewkowich IP, et al. The cationic amino acid transporter 2 regulates inflammatory homeostasis in the lung. Proc. Nat. Acad. Sci. (103): 14895-14900, 2006
Lewkowich IP, et al. Enhanced allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice. PLoS ONE. (3): e3879, 2008
Zhang X, Lewkowich IP, al. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J. Immunol. (182): 5123-5130, 2009
Lewkowich IP, et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat. Immunol. (10): 928-935. 2010. -
Philana Lin, MD
University Of Pittsburgh, Pittsburgh, PA
Biomedical Research GrantFine-Tuning the Immune System to Help Fight TB
Previous research has suggested that while a strong immune system response is important in destroying the bacteria, it can also be harmful to the body, making a person feel very sick or even causing death. Immune cells called regulatory T cells are responsible for dampening the immune response, and thus play an important role in balancing the response to infection. The researchers will examine a subset of regulatory T cells that are involved in sending inflammatory cells to the site of infection. Understanding how these cells function in response to M. tuberculosis infection will provide important information on how best to fine-tune the immune system. Results of these studies could lead to improved vaccine and treatment strategies.
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Christopher Maher, PhD
Washington University, St. Louis, MO
Biomedical Research GrantIdentifying Genetic Mutations in Lung Cancer Patients
About half of lung cancer patients have been shown to have mutations that may be responsive to existing therapies. Recent technological advances have made it possible to comprehensively study genetic sequencing for all lung cancer patients, with an approach called highthroughput sequencing. However, this technology produces an immense amount of data, and scientists are faced with the challenge of identifying the sub-set of relevant mutations. This makes it difficult to translate discoveries from high-throughput sequencing into real-world applications to benefit patient care. Dr. Maher will attempt to develop a computational approach to identify and prioritize critical genetic sequences from a set of lung cancer patients, including those who have never smoked. The overall goal is to find new diagnostic markers and help determine which patients will respond to therapy.
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Nilam Mangalmurti, MD
University Of Pennsylvania, Philadelphia, PA
Biomedical Research GrantPreventing Acute Lung Injury After Transfusions
Red blood cell (RBC) transfusions routinely given in the intensive care unit (ICU) have been associated with the development of acute lung injury (ALI), and increased death rates in the critically ill. Dr. Mangalmurti hopes to define the way in which RBC transfusions worsen lung injury in the critically ill by examining whether transfusion of stored RBCs sensitizes cells in the blood vessels of the lung to subsequent injury. She will also look at whether RBCs increase production of a protein called RAGE, which promotes inflammation in the lung. Understanding how RBC transfusions increase RAGE and worsen ALI may lead to strategies to prevent lung injury associated with transfusions. Knowledge derived from these studies may lead to specific therapies, such as blocking activation of RAGE in cells of the blood vessels, or modifying storage methods to prevent the development of ALI associated with transfusions.
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Joshua Mezrich, MD
University of Wisconsin, Madison, WI
Biomedical Research GrantPreventing Environmentally Triggered Asthma Flareups
While it has long been known that certain environmental hazards can affect airway disease such as asthma, the way in which some of these toxins cause harm has been unclear. Joshua Mezrich, MD, is researching polycyclic aromatic hydrocarbons, toxic chemicals released into the environment by fossil fuel combustion. A primary route of human exposure to these chemicals is tobacco smoke. He hopes that his investigation will identify an entirely new target for intervention, both before and after environmental exposures, to prevent worsening of airway disease.
“If you can identify people at risk of developing disease before they do so, you might be able to minimize their exposure, or treat them before they develop the disease.”“It’s possible that if people are exposed to toxins over a long period, they could alter the immune system,” says Dr. Mezrich. “We are exposed to many of these toxins through pollutants such as cigarette smoke and diesel fuel, all of which are associated with aggravating asthma.”
He is focusing on the receptor through which these hydrocarbons work, known as Aryl Hydrocarbon Receptor (AHR). He screened many small compounds to see which ones activate AHR strongly, and found a few that were not previously known to do so. One of the compounds was designed as a cancer drug that blocks growth of blood vessels in tumors. Dr. Mezrich found the compound activates AHR and helps regulate the immune response. “Although it did not work well against cancer, clinical tests showed it was tolerated, so it could be tested safely for asthma,” he notes.
“If we can prove one of the mechanisms of airway disease involves activation of AHR by environmental exposures, it would open up new ways of regulating this process,” Dr. Mezrich says. He suggested that an inhaled treatment could be developed to modulate the effects of toxins that cause problems in airway disease.
He also hopes to be able to identify which people are at risk from toxic exposures, by looking at their activation of AHR in response to these exposures. “If you can identify people at risk of developing disease before they do so, you might be able to minimize their exposure, or treat them before they develop the disease,” he says. “We hope this research will be very translatable.”
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Christopher Migliaccio, PhD
University of Montana, Missoula, MT
Biomedical Research GrantInvestigating Wood Smoke’s Effect on the Lungs
Macrophages are considered to be the first line of defense in the lung, due to their primary function of engulfing and clearing out inhaled particulates that bombard the lungs. Macrophages usually engulf inhaled particulates and clear them from the lungs. However, some particulates can kill or alter the function of macrophages. One such exposure may be wood smoke inhalation from wood stoves, forest fires, and cooking. Wood smoke is a major contributor to particulate matter in many areas throughout the U.S. and the world. Dr. Migliaccio has found that in mice, there is a decrease in bacterial clearance from the lungs following inhalation of wood smoke and as such, will study the effects of inhaled wood smoke on lung macrophages. His research will generate knowledge to deepen understanding of the health effects of wood smoke, and its adverse effects on the lung’s immune response. It could also generate powerful targets for therapeutic treatments of smoke exposures.
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Seyed Javad Moghaddam, MD
University of Texas M.D. Anderson Cancer Center
Lung Cancer Discovery Award 2009-2011Airway Inflammation’s Role in Lung Cancer
Many studies have found that smokers with chronic obstructive pulmonary disease (COPD) have an increased risk of lung cancer compared with smokers with comparable cigarette exposure but without the disease. COPD causes inflammation in the lung, which persists even after a person stops smoking. These facts suggest a link between chronic airway inflammation and lung cancer, but the precise way in which the link works is unknown. It may be a genetic variation in the immune system’s inflammatory response to inhaled smoke and to microorganisms that gather in the airways of smokers.
Publications:Through a Lung Cancer Discovery Award, funded in partnership between the American Lung Association and the LUNGevity Foundation, Dr. Moghaddam used a mouse model to study the mechanism responsible for promotion of lung cancer by airway inflammation. He concentrated on a genetic alteration found in COPD and lung cancer, involving a gene called NF-kB and the protein it produces, interleukin 6 (IL-6). Dr. Moghaddam was able to show that COPD-like airway inflammation promotes lung cancer in a mouse model. He found mice whose NF-kB or IL-6 gene was switched off in the airway had a 70% reduction in the number of tumors induced on the surface of the lung compared with mice whose NF-kB or IL-6 gene was not turned off.
Ochoa CE, Mirabolfathinejad, SG, Ruiz VA, Evans SE, Gagea, M, Evans CM, Dickey CF, Moghaddam SJ (2011) Interleukin 6 but Not T helper 2 Cytokines Promotes Lung Carcinogenesis.Cancer Prev Res 4(1):52-64.
This research could lead to development of antiinflammatory therapy in patients with COPD who are at high risk for lung cancer, and in patients with early stage lung cancer.
Dr. Moghaddam was able to use data from this project to apply for and receive a larger grant on dissecting the role of airway inflammation in lung cancer promotion. -
Sean Vincent Murphy, PhD
Wake Forest University Health Sciences, Winston-Salem, NC
Senior Research Training FellowshipDeveloping a Cell Therapy for Cystic Fibrosis
Stem cells in amniotic fluid called fetal stem cells may one day be used to treat babies born with cystic fibrosis (CF). Sean Vincent Murphy, PhD, is using an American Lung Association Senior Research Training Fellowship grant to develop cell therapy that can be used to improve the function of abnormal lung cells in CF patients.
“We’re ‘working out’ the cells so they’re tough enough to survive in the lung environment.”Patients with cystic fibrosis have a defect in a gene that allows for proper regulation of salts and water in various tissues. This alteration causes significant problems in the lungs of people with CF. The normal mucus in the lungs becomes thick and dehydrated, and ultimately blocks the airway passages, resulting in a predisposition towards chronic bacterial infections and lung disease.
Dr. Murphy and colleagues have discovered a small number of stem cells in amniotic fluid and placental tissue, called fetal stem cells, which represent an intermediate stage between embryonic stems cells and adult stem cells. Fetal stem cells give rise to many of the specialized cell types found in the human body. They are easily obtainable, since they are found in leftover birth tissue, and can be grown in large quantities—they typically double in number every 36 hours.
The researchers will first attempt to produce functional lung fluid exchanging cells from fetal stem cells. “We will prepare cells for the stresses they will face when they get into the lungs,” Dr. Murphy says. “We place them on a flexible surface that is stretched in a way that’s similar to how lungs stretch during breathing. We’re ‘working out’ the cells so they’re tough enough to survive in the lung environment.”
They will then try to replace the function of lung cells damaged by experimental radiation with fetal stem cells, to see if they can significantly improve function to the dysfunctional lung. They performed studies in which they gave mice a dose of radiation to damage their lung cells. They found that when they administered fetal stem cells through a tube via the trachea or nose, a significant number of cells were successfully implanted in the lungs.
Dr. Murphy says that if the treatment is eventually found to be safe and effective in humans, the treatment could be given to newborns known to have cystic fibrosis through a tube down the trachea—the same type of tube used to inflate the lungs of newborns who are having difficulty breathing.
“If we were to use the babies’ own cells, we would use gene therapy on the stem cells to repair the damage and then return them to the patient,” he says. “However, we wouldn’t necessarily need to use the patients’ own cells—we can develop large banks of fetal stem cells to be used when they are needed.” -
Fumihiko Namba, PhD, MD
Children’s Hospital Of Philadelphia, Philadelphia, PA
Senior Research Training FellowshipProtecting New Lungs from Damage by Oxygen
Most newborn babies who are born prematurely or who experience respiratory problems shortly after birth need supplemental oxygen. The exposure to excess oxygen, called hyperoxia, can cause lung injury and abnormal development of lung tissue. An enzyme called heme oxygenase-1 (HO-1) has been shown to protect against cell death. Although HO-1 is normally found in the cell’s cytoplasm, it migrates to the nucleus in the lungs of newborn mice exposed to excess oxygen and is likely to play a role in DNA repair. The researchers will study whether HO-1 protects against hyperoxia in the newborn lung by examining the effects of HO-1, found in the nucleus of lung cells, on DNA damage and repair in mice genetically engineered to produce excessive amounts of HO-1. After the mice are exposed to excess oxygen for 72 hours, their lungs will be evaluated, with special attention given to enzyme activity, lung development and DNA damage. Understanding HO-1’s function and its role in hyperoxia in the newborn lung may lead to treatments to protect newborn babies against lung damage caused by hyperoxia.
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Toru Nyunoya, MD
Biomedical Research Institute of New Mexico, Albuquerque, NM
Biomedical Research GrantCigarette Smoke Affects Lungs’ “Biological Clock”
Exposure to cigarette smoke increases the risk of emphysema. One possible mechanism may be that contents of smoke shorten the length of telomeres, the ends of chromosomes that function as protectors, and control the process by which each cell ages. Each time a cell splits, some telomere is lost making the lungs vulnerable to emphysema. This telomere “biological clock” is maintained by a protein called Werner’s syndrome protein (WRN), which repairs DNA. Dr. Nyunoya has found that cigarette smoke exposure causes cell aging by WRN protein loss. His research will examine how cigarette smoke decreases WRN protein and advances the biological clock in the lung. Based on the mechanisms identified by this research, Dr. Nyunoya plans to develop a novel treatment for emphysema.
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Minal R. Patel, MPH
University of Michigan, Ann Arbor, MI
Lung Health Dissertation GrantTalking to the Doctor About the Cost of Managing Asthma
Some people may experience problems with the cost of managing their asthma due to reasons that may not necessarily have to do with having health insurance or the means to pay for health care. Ms. Patel will see if women who talk to their doctor about asthma-related financial concerns have better asthma outcomes and will investigate what kinds of patients experience cost-related problems with their asthma management and want to talk about this with their doctor. Ms. Patel will also study what factors related to asthma cause patients to experience cost-related problems, and if talking to a doctor about cost is related to how people manage their asthma and their use of health services. The results of the study may help design programs for doctors and other health care providers that teach them how to talk about cost with their patients, especially African American women who experience the most problems with asthma management.
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Jose Perez-Zoghbi, PhD
Texas Tech University, Lubbock, TX
Biomedical Research GrantNew Clues to Airway Narrowing in Obstructive Lung Disease
A characteristic of asthma and other lung diseases such as chronic obstructive pulmonary disease (COPD) is the excessive narrowing of the airways in response to stimuli. The narrowing of the airways is produced by a contraction in the muscle that surrounds the airways. Chemical signals within the muscle regulate its contraction. The researchers will investigate how these signals regulate the contraction of the muscle and how they are affected during disease. They will use a mouse model of asthma that does not respond to current drug treatments. They will compare the response of stimuli in the airways of these mice to the response in airways of healthy mice. This knowledge can be used to help in the design of new treatments of obstructive lung disease.
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Daniela Petrusca, PhD
Indiana University, Indianapolis, IN
Biomedical Research GrantCigarette Smoke’s Role in Emphysema
The clearance of dead cells from the lungs is an important process that protects tissues from the toxic contents of dying cells, which may cause damage to the surrounding tissue and may produce inflammation. The lungs possess specialized immune cells called macrophages that are responsible for engulfing the dying cells. Cigarette smoke exposure, however, impairs this function. Cigarette smoke also introduces a special state of “self-protection” that when functioning properly, helps the cell live in harsh conditions. But chronic cigarette smoke exposure alters this self-protection mechanism. Dr. Petrusca will study the mechanism that links the impairment caused by cigarette smoke in the cleaning up of dying cells to the alterations in the cells’ self-protection state. The results may lead to potential targets of emphysema treatment.
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Venuprasad Poojary, PhD
Wayne State University, Detroit, MI
Biomedical Research GrantUnderstanding How Lung Inflammation Leads to Cancer
Lung cancer is the major cause of cancer-related deaths for both men and women in the United States. Lung inflammation associated with chronic obstructive pulmonary disease (COPD), cigarette smoking, exposure to asbestos and silica is closely linked to the development of lung cancer. However, the molecular mechanisms that link lung inflammation and cancer progression remain unclear. Dr. Poojary hopes to better understand a novel regulatory mechanism in the inflammatory cells which plays a critical role in the termination of tumor-promoting inflammation. The information obtained from these studies could lead to therapeutic interventions to target inflammatory cells in the tumor.
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Lee Quinton, PhD
Harvard University School of Public Health
Senior Research Training Fellowship 2006-2008Targeting the Immune System’s Response to Bacterial Pneumonia
Respiratory infection is a leading cause of lung injury and death in the United States. Due to their small size, potentially harmful agents such as bacteria can circumvent initial airway filtration mechanisms, allowing them to invade lower regions of the lung. The body mounts an inflammatory response to bacterial colonization in order to direct the cells of the immune system toward infected airspaces. While this immune response is essential for the clearance of harmful bacteria, it must be precisely regulated in order to prevent lung injury, which can result from excessive inflammation.
Dr. Quinton studied a protein called signal transducer and activator of transcription-3 (STAT3) which is activated within cells during the immune response to lung infection. He hoped to identify factors in the lung that can activate STAT3 and determine the consequence of STAT3 deficiency during bacterial pneumonia.
With the help of his American Lung Association grant, he found that the presence of STAT3 in specific lung cells is required early during infection for promoting inflammation, and is also necessary for limiting inflammation and preventing lung injury at later times. In addition, he identified a previously unrecognized factor that may be most responsible for initiating STAT3 activity in response to lung infection.
The results of this study helped identify specific aspects of the immune system response during pneumonia that can be targeted for therapeutic intervention.Publications:
Quinton, L.J., Jones, M.R., Simms, B.T., Kogan, M.S., Robson, B.E., Wilson, C.B., Skerrett, S.J., and Mizgerd, J.P. (2006) Functions and regulation of NF-KB RelA during pneumococcal pneumonia. Journal of Immunology. 178: 1896-1903
Johnston R.A., Mizgerd J.P., Flynt L., Quinton, L.J., Williams E.S., and Shore S.A. (2007) Type I lnterleukin-1 Receptor is Required for Pulmonary Responses to Subacute Ozone Exposure in Mice. A J Respir Cell Mol Biol. 37: 477-484
Happel, K.I., Rudner, X; Quinton, L.J., Movassaghi, J.L., Clark, C., Odden, A.R., Zhang, P., Bagby, G.J., Nelson, S., and Shellito, J.E. (2007) Acute Alcohol Intoxication Suppresses the Pulmonary ELR-Negative CXC Chemokine Response to Lipopolysaccharide. Alcohol. 41: 325-333
Quinton, L.J., Jones, M.R., Robson, B.E., Simms, B.T., Whitsett, J.A., and Mizgerd, J.P. (2008) Alveolar epithelial STATS, IL-6 family cytokines, and host defense during Escherichia coli pneumonia. American Journal of Respiratory Cell and Molecular Biology. 38: 699-706
Gamble, L., Bagby, G.J., Quinton, L.J., Happel, K.I., Mizgerd, J.P., Zhang, P., and Nelson, S. (2008) The systemic and pulmonary lipopolysaccharide binding protein response to intratracheal lipopolysaccharide. Shock 31: 212-7
Quinton, L.J., Jones, M.R., Robson, B.E., and Mizgerd, J.P. (2009) Mechanisms of the hepatic acute phase response during bacterial pneumonia. Infection and Immunity 77: 2417-26
Jones, M.R., Quinton, L.J., Blahna, M.T., Neilson, J.R., Fu, S., Ivanov, A.R., Wolf, D.A., and Mizgerd, J.P. (2009) Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nature Cell Biology 11:1157-63.
Quinton, L.J. and Mizgerd, J.P. (2011) NF-κB and STAT3 signaling hubs for lung innate immunity. Cell and Tissue Research 343(1): 153-65
Pittet, L.A., Quinton, L.J., Yamamoto, K., Robson, B.E., Ferrari, J.D., Algül, H., Schmid, R.M., and Mizgerd, J.P. (2011) Earliest innate immune responses require macrophage RelA during pneumococcal pneumonia. American Journal of Respiratory Cell and Molecular Biology 45(3): 573-81
Zamjahn, J., Quinton, L.J., Mack, J., Frevert, C., Nelson, S., and Bagby, G.J. (2011) Differential flux of macrophage inflammatory protein-2 and cytokineinduced neutrophil chemoattractant from the lung after intrapulmonary delivery. American Journal of Physiology: Lung Cellular and Molecular Biology 301: L568-74
Blahna, M.T., Jones, M.R., Quinton, L.J., Matsuura, K.Y., and Mizgerd, J.P. (2011) The terminal uridyltransferase enzyme zinc finger CCHC domain containing 11 (ZCCHC11) promotes cellular proliferation independent of its uridyltransferase activity. Journal of Biological Chemistry 286(49): 42381-9
Quinton, L.J. (2012) GM-CSF: A double dose of protection during pneumonia. American Journal of Physiology: Lung Cellular and Molecular Biology (Epub ahead of print)
Quinton, L.J., Blahna, M.T., Jones, M.R., Allen, E., Hilliard, K.L., Ferrari, J.D., Zhang, X., Sabharwal, V., Algül, H., Akira, S., Schmid, R.M., Pelton, S.I., Spira, A., and Mizgerd, J.P. (2012) Combined hepatocyte-specific targeting of NF-κB RelA and STAT3 abrogates the acute phase response in mice. Journal of Clinical Investigation 122(5): 1758-63
Quinton, L.J., Mizgerd, J.P., Hilliard, K.L., Jones, M.R., Kwon, C.Y., and Allen, E. (2012) Leukemia inhibitory factor signaling is required for lung protection during pneumonia. Journal of Immunology 188(12): 6300-8
Yamamoto, K., Ferrari, J.D., Cao, Y., Ramirez, M.I., Jones, M.R., Quinton, L.J., and Mizgerd, J.P. (2012) Type I alveolar epithelial cells mount innate immune responses during pneumococcal pneumonia. Journal of Immunology (In Press) -
Einat Rabinovich, MD
University Of Pittsburgh, Pittsburgh, PA
Senior Research Training FellowshipMolecular Strategies to Treat Excessive Lung Scarring
Studies have shown that even decades after an initial environmental exposure, changes in the lung continue in people with idiopathic pulmonary fibrosis (IPF). The researchers will use technologies that allow genetic profiling to study the role of genetic changes in the abnormal IPF lung. Their focus will be the role of a process called DNA methylation in the development of IPF. DNA methylation is a naturally occurring chemical modification of DNA often caused by environmental and occupational factors, which can induce changes in the regulation of cells. Gaining a better understanding of DNA methylation’s role in IPF could lead to the discovery of new molecular targets for therapy, better use of available drugs, and improvements in diagnosis and management of IPF.
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Sammeta Vamsee Raju, PhD
University of Alabama, Birmingham, AL
Senior Research Training FellowshipNeutralizing Acrolein, a Cigarette Smoke Toxin
Chronic bronchitis is caused by cigarette smoking and long-term exposure to air pollutants. People with chronic bronchitis suffer from delayed mucus clearance. Therapy for chronic bronchitis is largely limited to oxygen and bronchodilators. These therapies only provide symptomatic relief without correcting the underlying factors, which are still not very well understood. Recently it has been discovered that cigarette smoke causes cystic fibrosis-like defects in CFTR, a gene that is defective in cystic fibrosis and causes reduced mucus clearance in the lungs, increased lung infections and bronchitis—symptoms similar to some identified with COPD. Dr. Raju will study the extent and severity of CFTR dysfunction by cigarette smoke in a mouse model and its contribution to chronic bronchitis. He will test how acrolein, a respiratory toxin present in cigarette smoke, could influence respiratory health, including its effect on CFTR and mucus transport. Dr. Raju will also investigate whether acroleinneutralizing drugs can reverse defective CFTR and mucus transport in smokers.
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Roxana E. Rojas, MD, PhD
Case Western Reserve University
Biomedical Research Grant 2007-2009Gaining Insight into How TB Germ Hides From Immune System
While one-third of the world’s population is currently infected with TB, only about 10 percent of these people will develop TB disease in their lifetime. The remaining 90 percent have what is called latent or inactive TB, meaning their immune system can successfully fight the infection. The TB infection may remain inactive for a lifetime, although latent TB infection can become active if the person’s immune system becomes weakened (such as with HIV infection).
Roxana E. Rojas, MD, PhD, used an American Lung Association Biomedical Research Grant to investigate how the bacteria that causes TB, Mycobacterium tuberculosis, escapes recognition by the immune system and remains latent. Her goal was to gain information that could be used to design better vaccines.
M. tuberculosis appears to inactivate two types of key immune cells: macrophages and T lymphocytes. The TB bacteria primarily reside in macrophages, immune cells that engulf foreign material. Macrophages are activated by proteins called cytokines, which are secreted by T lymphocytes. Dr. Rojas studied the mechanisms that M. tuberculosis uses to inactivate T lymphocytes. She focused on molecules called glycolipids on the surface of the bacteria that affect T lymphocytes. Glycolipids prevent optimal interaction between T lymphocytes and macrophages, which is very important for the development of an effective immune response. In addition, mycobacterial glycolipids directly inactivate T cells, contributing to immune evasion.
Dr. Rojas made substantial progress toward her longterm goal of identifying and characterizing mycobacterial molecules that have a direct regulatory effect on T cell function. During the course of her research, she refined and expanded her original experiment to study the role of molecules other than the one she originally focused on. “This ALA-funded project and follow up studies stemming from it will have a direct impact in vaccine development,” she says. “These findings will help design improved anti- TB vaccines and therapeutic measures to limit TB damage in the lung.”
Since completing her research funded by the American Lung Association, Dr. Rojas received two grants from the National Institutes of Health.Publications:
C.L. Lancioni, J.J. Thomas and R.E. Rojas Activation requirements and responses to TLR ligands in human CD4+ T cells: comparison of two T cell isolation techniques. J Immunol Methods. 2009 May 15;344(1):15-25.
S. Mahan, J. J. Thomas, W. H. Boom and R. E. Rojas. (2009). CD4(+) CD25(high) Foxp3(3+) regulatory T cells downregulate human Vdelta2(+) T-lymphocyte function triggered by anti-CD3 or phosphoantigen. Immunology. 127(3): 398-407.
Mahon R. N., Rojas R. E., Fulton S. A., Franko J., Harding C. V. and Boom W. H. (2009). Mycobacterium tuberculosis cell wall glycolipids directly inhibit CD4+ T-cell activation by interfering with proximal T-cell-receptor signaling. Infect. Immun., 77(10): 4574-83.
Drage, M.G., Tsai, H.-C., Pecora, N.D., Cheng, T.-Y., Arida, A.R., Shukla, S., Rojas, R.E., Moody, D.B., Boom, W.H., Sacchettini, J.C., and Harding, C.V. (2010). Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2. Nature Struct Mol Biol. 17: 1088-1095.
Christina L. Lancioni, Qing Li, Jeremy J. Thomas, Xuedong Ding, Bonnie Thiel, Michael G. Drage, Nicole D. Pecora, Assem G. Ziady, Samuel Shank, Clifford V. Harding, W. Henry Boom and Roxana E. Rojas. (2011). Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4+ T cell activation via TLR2/1. Infection and Immunity. 79 (2): 663-673.
Robert N. Mahon, Obondo J Sande; Roxana E Rojas, Alan D Levine, Clifford V Harding, Henry Boom. 2012. Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation. Cell Immunol. 275(1-2): 98-105.
Qing Li, Xuedong Ding, Jeremy J. Thomas, Clifford V. Harding, Nicole D. Pecora, Assem G. Ziady, Samuel Shank, W. Henry Boom, Christina L. Lancioni and Roxana E. Rojas. 2012. Rv2468c, a novel Mycobacterium tuberculosis protein that co-stimulates human CD4+ T cells through VLA-5. J Leukoc Biol. 2012 Feb; 91(2): 311-2. -
Vikram Saini, PhD
University of Alabama, Birmingham, AL
Senior Research Training FellowshipLink Between Cigarette Smoke and Multi-Drug Resistant Tuberculosis
Multi-drug resistant TB (MDRTB) is a particularly dangerous form of TB, as it is resistant to two of the most powerful anti-TB drugs. While MDR-TB is generally treatable, it requires up to two years of treatment with secondline anti-TB drugs. There is evidence that tobacco smoking is associated with an increased risk of TB infection, disease, reactivation and death. Many countries with a high prevalence of TB also have a high prevalence of smoking. However a link between cigarette smoking and MDR-TB has not yet been established. Dr. Saini has already shown that harmful components of cigarette smoke mutate the DNA of tuberculosis-causing bacterium Mycobacterium tuberculosis (Mtb). Some of these mutations are in genes that confer drug resistance to Mtb. Dr. Saini will use a mouse model to examine whether exposure of Mtb cells to cigarette smoke leads to the development of MDR-TB. This research will result in a better understanding of the link between tobacco smoke and TB drug resistance.
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Lobelia Samavati
Wayne State University, Detroit, MI
Biomedical Research GrantHow Immune System Works Differently in Sarcoidosis
Sarcoidosis is an inflammatory disorder that can affect multiple organs throughout the body. Its is unknown what causes the disease and its course and outcome are difficult to predict in each individual patient. Immune protein cells in the body are equipped to recognize these invaders, triggering an inflammatory response in an attempt to kill the invading foreign pathogens. In healthy individuals, inflammation shuts down once an infection is fought off; however, this process remains sustained in sarcoidosis patients. Dr. Samavati will investigate why these immune proteins work differently and how the inflammatory process continues to be activated in sarcoidosis patients compared to healthy individuals. The findings may lead to more effective drug therapies.
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Jessica Seeliger
State University of New York, Stony Brook, NY
Biomedical Research GrantTargeting Latent and Multi-Drug Resistant TB
Mycobacterium tuberculosis (Mtb), the bacterium that causes TB in humans, infects one-third of the world’s population. Other lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer, as well as risk factors such as smoking, have been linked to an increased risk of developing TB. Most infected individuals have latent TB infections and have no symptoms. However, decreased immune responses, for example due to smoking or cancer treatment, can trigger latent TB to reactivate and cause infectious disease. Unfortunately, some TB disease can become resistant to first line medications and therefore, new therapies are needed to treat multi- and extremely drug-resistant TB strains. Dr. Seeliger will use a novel chemical method to evaluate a family of Mtb enzymes that have diverse functions essential for bacterial survival as potential drug targets. These enzymes may be promising for developing next-generation therapies against latent infections and multi-drug resistant TB.
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Debasish Sen, PhD
University Of California, San Francisco, San Francisco, CA
Senior Research Training FellowshipNovel Imaging Technique Answers Questions About Allergen-Induced Asthma
Although there are many asthma treatments, new therapies are needed to alter the long-term sensitivity of the immune system to environmental allergens. Dr. Sen will directly observe asthmatic lungs’ inflammatory response to allergens. He will use a novel technique called two-photon imaging, which allows for the visualization of single cells, to determine how and where cells in the lungs called antigen-presenting cells assist in aggravating inflammatory responses to asthma. His hope is to develop strategies for targeted inhibition of these asthma-aggravating cells, and initiate research toward the development of effective anti-inflammatory long-term asthma therapies.
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Jessica Sieren
University of Iowa, Iowa City, IA
Lung Cancer Discovery AwardIdentifying Which COPD Patients are Most at Risk of Lung Cancer
The risk of lung cancer is significantly higher in people with chronic obstructive pulmonary disease (COPD), independent of their smoking history. While chronic inflammation is thought to play a role, it is not known which people affected by COPD are most susceptible to developing lung cancer. Dr. Sieren will use computed tomography (CT) scans to generate anatomic measurements of lung tissue for each lobe of the lung, as well as each airway, down to the very small airway branches. These measurements can provide a highly detailed structural assessment of COPD and may be useful as biomarkers of cancer risk. These results will determine if an identifiable subgroup of COPD patients is associated with lung cancer formation. The biomarkers also may add new information that can help identify which lung nodules are likely benign or malignant. Dr. Sieren hopes to identify the subset of COPD patients most at risk for developing lung cancer and implement targeted detection and preventive treatments in order to minimize this cancer risk.
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Genee Smith, MSPH
University Of North Carolina, Chapel Hill, NC
Lung Health Dissertation Grant, American Lung Association Behavioral Risk Factor ScholarDoes Air Pollution Increase the Risk of Developing TB?
While some studies in mice have suggested a possible link between tuberculosis and air pollution, this question has not been studied on a large scale in humans. Previous research suggests that air pollution may increase the risk of developing TB by increasing inflammation in the lungs and decreasing the immune system’s response. The link between tuberculosis and smoking is also unclear, with some research showing an association and some not finding a connection. Ms. Smith will link two major sources of information: electronic medical records from the Kaiser Permanente patient database and air pollution data from the California Air Resources Board (CARB) to examine whether the association between air pollution and TB is stronger among smokers than nonsmokers. The results of the study could have global implications, since many developing countries have both high rates of TB and severe air pollution.
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Christina Stallings, PhD
Washington University, St. Louis, MO
Biomedical Research GrantHow Protein Helps TB Bacteria Stand Up to Immune System’s Assaults
Mycobacterium tuberculosis (Mtb), which infects one-third of the world’s population, caused an estimated 1.4 million TB-related deaths in 2010. This health crisis is worsened by the alarming emergence of drug-resistant strains.
“We will apply for funding for a larger National Institutes of Health grant based on everything we’ve done so far, which we hope will lead to new drug targets for TB.”During infection, mycobacteria must withstand an arsenal of assaults by the body’s immune system. “Mtb is a pretty amazing pathogen,” says Christina Stallings, PhD. “It can infect people for their entire lives, even if they have a robust immune system that fights it.” That is because Mtb has its own defenses that fight the immune system, she explains.
Using an American Lung Association Biomedical Research Grant, Dr. Stallings is studying how Mtb defends itself. She is focusing on a protein called mycobacterial CarD, which regulates the response of Mtb to assaults by the immune system, and is essential for acute and persistent infection.
Dr. Stallings has found that when a mutant form of Mtb that has less CarD is exposed to immune system assaults, the bacteria is much more sensitive and dies much faster. “That showed us that Mtb absolutely needs CarD to combat these stresses imposed by the immune system,” she says. She then used this strain of Mtb and infected mice with it. She found that the mouse immune system was able to kill the bacteria.
In the second year of her grant, Dr. Stallings is studying the mechanism by which CarD helps Mtb fight the immune system. “If we can figure out how it works, we could target it with new antibiotics and chemicals to compromise its activity,” she says.
The American Lung Association grant has been instrumental in her research, she says. “The grant has allowed us to characterize the protein, produce a mutant version of Mtb and bring it to a mouse model. We will apply for funding for a larger National Institutes of Health grant based on everything we’ve done so far, which we hope will lead to new drug targets for TB.” -
Martin Steffen, MD, PhD
Boston University
Biomedical Research Grant 2007-2009Study on Protein and Lung Disease Reveals Surprises
Dr. Steffen’s Biomedical Research Grant from the American Lung Association originally focused on the role of a protein called proteasome in chronic obstructive pulmonary disease (COPD). Proteasome is a key protein complex known to regulate several processes that cause inflammation, and which has previously been implicated in the development of diabetes and heart disease.
Publications:He isolated proteasome complexes from people with and without COPD, in order to identify differences between the two groups. He compared the protein and chemical composition of the complexes, and tested their functional activity. He was unable to consistently identify differences in protein composition between the two groups.
Wu CJ, Cai T, Rikova K, Merberg D, Kasif S, Steffen M. “A predictive phosphorylation signature of lung cancer” PLoS One. 4(11):e7994 (2009 Nov 25).
Fortunately, during his research, he was able to start a very successful line of inquiry on lung cancer. Dr. Steffen’s research centered on a process called phosphorylation, which can turn a protein “on” or “off.”
He identified a number of proteins whose activation allows them to distinguish between cancer cells and normal cells with almost 97 percent accuracy. He also developed a new way to identify key biological pathways that are active in cancer, but not in normal cells. He says his findings will ultimately lead to the development of drugs aimed at inhibiting these cancer-related pathways.
“Despite the fact that these studies represent a very significant departure from the originally proposed experiments, they are squarely aimed at reducing the burden of lung disease in patients, and illuminate biological mechanisms associated with the disease,” Dr. Steffen says.
He is now focused on developing a test to predict lung tumor sensitivity for the drug erlotinib. He hopes to expand this research to include other cancer drugs.
Based on his American Lung Association-funded research, Dr. Steffen applied for further grants to continue his investigations. -
Melissa Suter, PhD
Massachusetts General Hospital, Boston, MA
Biomedical Research Grant’Smart Needle’ Could Increase Accuracy of Early Lung Cancer Diagnosis
The survival of patients with lung cancer is directly related to the stage at which the cancer is detected. However, screening for lung cancer is only recommended in specific populations, partly due to difficulties in obtaining an accurate diagnosis following the identification of possible early cancers on CT screening techniques. Accurately locating nodules and taking a tissue sample for diagnosis is difficult, even when performed with advanced image guidance techniques. Dr. Suter plans to develop a new optical imaging tool that will increase the number of nodules that can be located and biopsied. This “smart needle” could lead to a reduction in potentially fatal delays in diagnosis and subsequent treatment in patients who may be falsely diagnosed as negative for lung cancer. This tool may also result in a reduction of unnecessary high-risk surgical procedures for the removal of nodules that currently cannot be biopsied.
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Omar Tliba, DVM, PhD
Thomas Jefferson University School of Pharmacy
Biomedical Research Grant 2007-2009Investigating Causes of Steroid-Resistant Asthma May Lead to New Treatments
Although most people with asthma respond to treatment with corticosteroids, these drugs don’t work in a substantial number of patients. Despite treatment with high doses of corticosteroids, these patients still have persistent lung inflammation and labored breathing, and are at increased risk of dying from asthma attacks.
Advances in understanding the mechanisms that are involved in the diminished action of corticosteroids will lead to the development of more effective therapy for patients who do not respond to steroids. In his American Lung Association-supported research, Dr. Tliba studied airway smooth muscle, a lung tissue that plays a key role in airway inflammation and bronchial hyper-responsiveness (airway “twitchiness”), two main features of asthma.
He hypothesized that chemical messengers called cytokines, which are released by immune cells in response to asthma triggers such as allergens and viruses, reduce the actions of corticosteroids in airway smooth muscle. Dr. Tliba discovered that a molecule called IRF-1 is involved in this process. His research suggests that increasing levels of IRF-1 may represent a novel therapeutic target for treating steroid-resistant asthma.
He then found that steroid resistance induced by protein chemical messengers called cytokines in airway smooth muscle could be reversed by vitamin D. The findings suggest that vitamin D also may exert some beneficial effects in the treatment of steroid-resistant proteins in patients with difficult-to-treat asthma. His research is likely to bring new insight into the development of novel therapeutic treatment of steroid-resistant asthma.
The American Lung association Biomedical Research Grant helped Dr. Tliba to apply for and receive a grant from the National Institutes of Health to study the mechanisms of inflammation-induced steroid resistance in asthma.Publications:
Damera G, Fogle HW, Lim P, Goncharova EA, Zhao H, Banerjee A, Tliba O, Krymskaya VP, Panettieri RA Jr. Vitamin D inhibits growth of human airway smooth muscle cells through growth factor-induced phosphorylation of retinoblastoma protein and checkpoint kinase 1. Br J Pharmacol. 2009 Nov; 158(6): 1429-41.
Bhandare R, Damera G, Banerjee A, Flammer JR, Keslacy S, Rogatsky I, Panettieri RA, Amrani Y, Tliba O. Glucocorticoid receptor interacting protein-1 restores glucocorticoid responsiveness in steroid-resistant airway structural ceils. Am J Respir Cell Mol Biol. 2010 Jan;42(l):9-15.
Goncharova EA, Goncharov DA, Damera G, Tliba O, Amrani Y, Panettieri RA Jr, Krymskaya VP. Signal transducer and activator of transcription 3 is required for abnormal proliferation and survival of TSC2-deficient cells: relevance to pulmonary lymphangioleiomyomatosis. Mol Pharmacol. 2009 Oct;76(4):766-77.
Bailey MT, Kierstein S, Sharma S, Spaits M, Kinsey SG, Tliba O, Amrani Y, Sheridan JF, Panettieri RA, Haczku A. Social stress enhances allergen-induced airway inflammation in mice and inhibits corticosteroid responsiveness of cytokine production. J Immunol. 2009 Jun 15;182(12):7888-96.
Clarke D, Camera G, Sukkar MB, Tliba O. Transcriptional regulation of cytokine function in airway smooth muscle cells. Pulm Pharmacol Ther. 2009 Oct;22(5):436-45.
Damera G, Tliba O, Panettieri RA Jr. Airway smooth muscle as an immunomodulatory cell. Pulm Pharmacol Ther. 2009 Oct;22(5):353-9.
Tliba O, Panettieri RA Jr. Noncontractile functions of airway smooth muscle cells in asthma. Annu Rev Physiol. 2009;71:509-35.
Tliba O. Panettieri RA Jr. Regulation of inflammation by airway smooth muscle. Curr Allergy Asthma Rep. 2008 May;8(3):262-8.
Banerjee A, Damera G, Bhandare R, Gu S, Lopez-Boado Y, Panettieri R Jr, Tliba O. Vitamin D and glucocorticoids differentially modulate chemokine expression in human airway smooth muscle cells. Br J Pharmacol. 2008 Sep;155(l):84-92.
Jain D, Keslacy S, Tliba O. Cao Y, Kierstein S, Amin K, Panettieri RA Jr, Haczku A, Amrani Y. Essential role of IFNbeta and CD38 in TNFalphainduced airway smooth muscle hyper-responsiveness. Immunobiology. 2008;213(6):499-509.
Tliba O. Amrani Y, Panettieri RA Jr. Is airway smooth muscle the “missing link” modulating airway inflammation in asthma? Chest. 2008 Jan;133(l):236-42.
Tliba O. Amrani Y. Airway smooth muscle cell as an inflammatory cell: lessons learned from interferon signaling pathways. Proc Am Thorac Soc. 2008 Jan 1;5(1):106-12.
Goncharova EA, Goncharov DA, Chisolm A, Spaits MS, Lim PN, Cesarone G, Khavin I, Tliba O, Amrani Y, Panettieri RA Jr, Krymskaya VP. Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation. Mol Pharmacol. 2008 Mar;73(3):778-88.
Tliba O, Damera G, Banerjee A, Gu S, Baidouri H, Keslacy S, Amrani Y. Cytokines induce an early steroid resistance in airway smooth muscle cells: novel role of interferon regulatory factor-1. Am J Respir Cell Mol Biol. 2008 Apr;38(4):463-72. -
Roger Tsien, PhD
University of California, San Diego, CA
Senior Investigator AwardRole of proteases in Asthma Inflammation
Dr. Roger Tsien is a Nobel Prize winner in chemistry who is using his expertise to bring a new perspective to the study of asthma. Dr. Tsien is the first recipient of the American Lung Association/American Asthma Foundation Senior Investigator Award, given to a non-pulmonologist conducting novel and innovative research on asthma.
“I am hopeful we can make a scientific discovery that could help develop a better understanding of a disease I have experienced personally.”Dr. Tsien will be focusing on the work of proteases, which are ubiquitous enzymes involved in many biological processes including the inflammation that underlies asthma. Little is known about precisely when and where different proteases become active in asthma. Dr. Tsien, Professor of Pharmacology and Chemistry & Biochemistry at the University of California, San Diego, will use an imaging technique already developed for cancer and apply it to proteases to better understand how they are involved in asthma.“We realized this imaging technique had many potential applications to other diseases, including atherosclerosis, or hardening of the arteries, which involves immune cells that are attacking blood vessels,” Dr. Tsien says. “ It will also apply to asthma, a disease in which immune cells attack lung cells.” The development of agents to target these enzymes for the treatment of asthma requires knowledge of exactly where, when and how they act in the lung. Dr. Tsien’s research, which will be conducted in an animal model, aims to answer these questions. Eventually, Dr. Tsien says the findings from the study could be applied to human patients for diagnosis and potentially for the evaluation of new treatments for asthma.
Dr. Tsien is eager to be studying asthma, which he has had since his childhood on the East Coast. “I suffered from allergic asthma as a child,” he says. “Since growing up and moving to California, I don’t suffer from allergy-induced asthma anymore, but I can still get exercise-induced asthma, and I carry an inhaler with me at all times. I am hopeful we can make a scientific discovery that could help develop a better understanding of a disease I have experienced personally.”
Dr. Tsien was a co-recipient of the 2008 Nobel Prize in chemistry, with Osamu Shimomura and Martin Chalfie, for the discovery and development of the green fluorescent protein, GFP. First observed in jellyfish, GFP has been used to develop ways to watch processes that were previously invisible, such as the development of nerve cells in the brain or how cancer cells spread. “That work, like my asthma research, was also related to imaging biological processes,” he says.
The American Lung Association/American Asthma Foundation Senior Investigator Award is a three-year award valued at $250,000 per year.
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Hoshang Unwalla, PhD
University Of Miami, Miami, FL
Biomedical Research GrantImproving Effectiveness of COPD Drugs
Acute flare-ups of COPD and asthma are treated with inhaled bronchodilators, which are available in an aerosolized form for inhalation. When inhaled, these drugs have to get through airway cells called epithelial cells in order to reach smooth muscle cells, which contract in people with obstructive lung disease. The bronchodilators cause the smooth muscle cells to relax, thus widening the airways. Dr. Unwalla has shown that one of the most commonly used bronchodilator drugs, albuterol, can enhance its own transport across epithelial cells to elicit a rapid onset of action on smooth muscle cells. He will study the basis of this action and determine if other inhaled bronchodilators demonstrate a similar ability. The information gained from this study could be used to devise better formulations and combinations of bronchodilators for effective treatment of COPD or devise alternative strategies in airway diseases where this pathway is afflicted.
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David Verhoeven, PhD
Rochester General Hospital, Rochester, NY
Biomedical Research GrantWhy Does Influenza Cause More Severe Illness in Young Children?
Children are particularly prone to and suffer from high rates of illness throughout the course of influenza infection than adults. The researchers will study possible mechanisms that account for this discrepancy. Using a mouse model, the researchers will compare the differences in the level of illness, as well as, the amount of inflammation and lung damage during influenza infection between infants and adults. Preliminary research suggests that the lungs of young children do not respond like those of adults during influenza infection. By further exploring the differences between infant and adult lung responses to infection, the researchers hope to gain a better understanding of what causes more severe illness in children infected with the influenza virus. These mechanisms might provide potential therapeutic or vaccination targets to limit or prevent the amount of lung tissue damage during infection of children.
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Carolien Wansleeben, PhD
Duke University Medical Center, Durham, NC
Senior Research Training FellowshipShedding Light on the Stem Cells of Mucus-Producing Glands
Airway diseases such as asthma, COPD and cystic fibrosis are characterized by an overproduction of mucus that causes airflow obstruction, setting the stage for respiratory infections. Mucus is produced by submucosal glands, small groups of cells that lie under the surface of the airways. In the diseased lung, the submucosal glands become enlarged and often produce more mucus. It is not known what controls the size and number of submucosal glands in the lungs, or what triggers their overgrowth in some conditions. Using a mouse model, Dr. Wansleeben will study the basic mechanisms of stem cell behavior in mucusproducing glands. Stem cells serve to renew tissue over time, and these cells play a role in controlling the structure of that tissue. The results will provide insight into the development of overgrowth of submucosal cells and could be useful in developing new targets for disease therapy.
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Kazuko Yamamoto, MD, PhD
Boston University, Boston, MA
Senior Research Training FellowshipFine Tuning the Lungs Response to Pneumonia Causing Bacteria
During a lung infection such as pneumonia, white blood cells called neutrophils are recruited from the blood into the air spaces of the lungs, where they are essential for clearing bacteria. But excess recruitment of these cells may cause acute lung injury. The coordination of this delicate inflammatory process requires a family of cell-signaling proteins called cytokines that regulate and maintain immune system activity. Creation of cytokines is initiated in large part by signaling from a protein called NF-kappaB. The researchers will study a specific type of NF-kappaB, to determine their role in the immune system’s response to pneumonia. The results of the study will help to identify specific aspects of the immune system that can be targeted in order to decrease illness and death caused by pneumonia. -
Jae-Kwang Yoo, PhD
University of Virginia, Charlottesville, VA
Senior Research Training FellowshipHow Immune Cells Come to the Rescue Against Influenza
Influenza viruses cause considerable illness and death. Each year, 5% to 20% of the population in the United States contracts influenza. Approximately 200,000 people are hospitalized and as many as 36,000 die from complications associated with seasonal flu. Jae-Kwang Yoo, Ph.D., is trying to gain a better understanding of how the body’s immune system fights the influenza virus. “We can use this information to improve the efficiencies of the vaccine for the seasonal flu, and potentially for a pandemic flu,” he says.
“We can use this information to improve the efficiencies of the vaccine for the seasonal flu, and potentially for a pandemic flu.”When a person is infected with the influenza virus, the immune system responds using B cells. These cells produce neutralizing antibodies that are essential both to prevent reinfection and to eliminate the infection from the respiratory tract. Once they are activated, B cells proliferate and differentiate, or become specialized. B cells are dependent on immune cells called CD4+ T cells to help with this process. A type of CD4+ T cells called T follicular helper cells (TFH) provide B cells with assistance in fighting influenza, but how these helper cells are generated against influenza is not well understood.
During his PhD training in the lab of Dr. Eleanor N. Fish at the University of Toronto, Dr. Yoo and colleagues identified a new cell involved in fighting against viruses called late activator antigen presenting cell (LAPC). This cell regulates the body’s antibody response, especially in influenza virus infection. Now at the University of Virginia, working with Dr. Thomas J. Braciale, Dr. Yoo has found that LAPCs are potent inducers of TFH response in influenza virus infection. However, the exact way in which the immune system controls this process is still not clear. This is what he aims to understand.
“With the prestigious support from the American Lung Association Research Award, we can be one step closer to be able to provide insights into how our immune system controls antibody response in pulmonary viral infection,” Dr. Yoo says. “Hopefully, my American Lung Association-funded research may provide a framework for the identification of novel targets for therapeutic vaccine development to prevent influenza A virus infection. This will ultimately help save lives.” -
Zbigniew Zaslona, PhD
University of Michigan, Ann Arbor, MI
Senior Research Training FellowshipDeciphering Macrophages’ Role in Asthma
Alveolar macrophages (AMs) are immune cells that play a pivotal role in the coordination of inflammatory responses in the lung. AM numbers are elevated in asthma, but the mechanisms responsible for this are poorly understood. Dr. Zaslona will study substances called eicosanoids which participate in many biologic processes, including inflammation. He will study the role of certain eicosanoids in controlling accumulation of AMs and their activation in asthma. Using a mouse model, Dr. Zaslona will investigate whether one eicosanoid, prostaglandin E2, decreases AM accumulation in asthma, while another one, leukotriene, increases it. The findings will provide new insight into macrophage regulation in allergic asthma. Since drugs that modify the actions of eicosanoids are already available or in development, their results may directly translate to improved therapies for asthma.
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Igor Zelko, PhD
University of Louisville, Louisville, KY
Biomedical Research GrantBlocking Remodeling in Lung’s Blood Vessels in Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a devastating disease; only about half of patients survive five years after diagnosis. The lung’s blood vessels are remodeled and constrict, leading to heart failure due to an enlarged and ineffective right side of the heart. Current drugs used to treat the disease enlarge the blood vessels, but do not block the eventual thickening of the artery walls and do not improve survival. More effective therapies are urgently needed.
“If it is successful, eventually this drug could be used in human trials to stop, or even reverse progression of the disease.”With the assistance of an American Lung Association Biomedical Research Grant, Igor Zelko, PhD, is studying the mechanisms that regulate remodeling of blood vessel walls in the lung. He is focusing on a substance that inhibits an enzyme called histone deacetylase, which he hopes will provide clues that could lead to better therapy for PAH.
A process called acetylation, or modification of histones regulates the expression of a major antioxidant enzyme in the pulmonary arteries. Dr. Zelko is investigating whether histone deacetylase inhibitors will significantly elevate levels of this antioxidant enzyme, called extracellular superoxide dismutase, which in turn will reduce or completely block remodeling of the lung’s blood vessel walls and slow or prevent the development of PAH in a mouse model.
“If it is successful, eventually this drug could be used in human trials to stop, or even reverse progression of the disease,” Dr. Zelko says.
He is particularly grateful to the American Lung Association for funding his research. “My startup funding had ended, and if I had not received the American Lung Association grant, I could not have continued this research, which I have been working on for the last 10 years,” he said. -
Zhenxiong Zhang, MD, PhD
Lovelace Respiratory Research Institute, Albuquerque, NM
Biomedical Research GrantPreventing Deadly Respiratory Problems Caused by Opioids in COPD Patients
Rapid shallow breathing (RSB) commonly occurs in patients with lung disorders such as chronic obstructive pulmonary disease (COPD). Compared to healthy people, patients with RSB are more prone to suffer respiratory depression and respiratory failure when they are given opioid painkillers such as fentanyl. This lifethreatening impact on breathing has markedly limited the use of these painkillers in patients with COPD. RSB is primarily generated by the stimulation of small nerve fibers in the lungs called pulmonary C-fibers (PCFs). PCFs can be stimulated when pulmonary inflammation, congestion, infection and accumulation of excessive fluid, or edema—characteristics of COPD—are present. Dr. Zhang has found that an intravenous injection of fentanyl switched RSB to a long-lasting breathing stoppage, or apnea, of up to five seconds in anesthetized rats. He hopes to understand how fentanyl makes this switch. The study may lead to discoveries that could be used to prevent and reduce the incidence of life-threatening respiratory depression by opioids, especially in patients with lung diseases.
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Jinming Zhao, PhD
University of Pittsburgh, Pittsburgh, PA
Biomedical Research GrantSuppressing Enzyme Involved in Asthma Activation
There is much that is still not known about how asthma develops. Dr. Zhao will focus on an enzyme called 15LO1 which has been found to be produced in large quantities in people with asthma, and is associated with inflammation and the development of other indicators of asthma such as mucus secretions. Dr. Zhao has found that inhibiting 15LO1 leads to decreased mucus secretion and a decrease in activation of a biologic pathway known to be involved in inflammation. Dr. Zhao will grow human airway cells and modulate 15LO1 activation, to better understand the enzyme’s role in asthma. This research could potentially lead to novel approaches to asthma treatment that suppress 15LO1 activation to dampen inflammatory processes. The findings could also apply to other related diseases.
