Roy Morello, PhD

Congenital (birth) defects in type I collagen, the most abundant protein in our body, give rise to Osteogenesis Imperfecta (OI – brittle bone disease). This is a disease that causes severe bone fragility as well as potential respiratory distress at birth and decreased respiratory function in adulthood. We will tease out the contribution of intrinsic (within the lung) versus extrinsic (outside of the lung, such as abnormalities in the chest wall and curvature of the spine) factors underlying the impaired breathing function in OI. We will also identify the alveolar cellular/molecular changes caused by type I collagen defects in animal models of OI. We will find out if intrinsic lung changes contribute significantly to breathing impairment in OI. This will provide a clearer understanding of the consequences of type I collagen mutations in the lung. Our goal is to identify new therapeutic targets and approaches to improve the overall health of patients with OI.S

Update:
We are on track with the proposed studies to determine the impact of type I collagen mutations/alterations on lung development and function, using mouse models of osteogenesis imperfecta (OI). We have successfully generated and also validated the first conditional knock-in mouse model for OI which can express a type I collagen mutation causing OI in a tissue-specific manner. This new model in year two  will allow us to determine the primary effects of a severe OI-causing mutation on the lung but in the context of a healthy skeleton (i.e. with intact chest cavity). In year two  we will also identify cellular and molecular changes in the lungs in a second mouse model of OI at 5 weeks of age compared to control mice.

Final Project Update:
We have been able to develop and validate a new mouse model of osteogenesis imperfecta (OI), a brittle bone disease that causes severe bone fragility as well as potential respiratory distress at birth and decreased respiratory function in adulthood. The model can express a type I collagen mutation that causes OI in the tissue of interest. This new model will allow a number of significant advances in the study of OI, including on the identification of its impact on the lung and respiratory function independent from its effects on the skeleton. 

The significant progress in our research, thanks to funds from ALA, led to the resubmission of an R01 application to the NIH to further expand these studies and that was successfully funded with a start date of September 01, 2023. We hope these studies, in the long term, will contribute to the development of new clinical recommendations for the pulmonology assessment and follow-up of patients affected with OI.