Quan Lu

Biomedical Research Grant: Genetic Tool May Help Explain Why Beta-Agonists Lose Their Effectiveness

Beta-agonists, the mainstay of asthma drugs, bind to the beta2-adrenergic receptor (b2AR) in the lung to relax smooth muscles and to reduce constriction in the airways. The medicine allows a person with asthma to breathe easier as the airway relaxes and gets bigger. But over time, beta-agonists become less effective. Many people with asthma find they have to take more and more of the drug in order to get relief from their asthma. This is because the receptors on the cells targeted by the drugs become degraded as they are bombarded by betaagonists repeatedly. This means that fewer and fewer receptors are available to lock onto the asthma drug. Eventually, the drug may stop working completely.

Quan Lu, Ph.D., is searching for genes that are involved in the degradation of these receptors. With a Biomedical Research Grant from the American Lung Association, Dr. Lu is using a powerful tool developed in his lab that inactivates genes one at a time in order to study which genes are involved in this degradation process. With the tool, they will screen all 28,000 human genes in a "gene inactivation library" in the lab. They will use cells that produce beta2 receptors in order to look for genes that are involved in degrading the receptors when flooded with beta-agonists.

"We know that some people respond better to beta-agonists than others, and we want to find those genetic differences that account for this," Dr. Lu says. "What’s exciting is that we could find genes that provide a target to improve beta-agonist therapy." He notes that this is the first step in a long process. "In later stages of the research we plan to study why certain genes are critical for beta-agonists’ response, and then eventually we would hope to develop a therapy based on this research that would increase beta2-receptors on cells so they would have a better response."