Walker and Colleagues Resubmit NIH R01 Application

Kudos to Julia Walker, professor; and her Multi-PI partners, Richard Bond of the University of Houston; Hong Wei Chu of the National Jewish Health System; and Raymond Penn of Thomas Jefferson University; and their entire team for the submission of their NIH R01 competing renewal application entitled "Optimizing Beta-Adrenoceptor Signaling Bias in Asthma." This proposal requests funding for a five-year period with a start date of Sept. 1, 2019.  

Agonists of the beta-2-adrenoceptor (β2AR), commonly referred to as β-agonists, have been a cornerstone of asthma treatment for nearly half a century. Despite their utility, β-agonists used in asthma management have problems, including functional tachyphylaxis, deterioration of asthma control, and mortality concerns. The inability to understand why such problems exist and the failure to significantly improve β2AR pharmacology is reflected by over 2 decades of NIH Program announcements declaring the need for safer, more efficacious alternatives to asthma treatment. Our recent published and unpublished studies provide compelling insight into why β-agonists are problematic while offering a solution to their clinical application. New data suggest that β2ARs transduce 2 qualitatively distinct signaling pathways in airway cells. The classic Gs-cAMP signaling pathway causes bronchocondilation and relief from breathlessness in asthmatics. However, the second signaling pathway is mediated by β-arrestin proteins and is associated with pro-inflammatory airway outcomes. Thus, this proposal hypothesizes that asthmatics may have reduced disease pathogenesis using β-agonists or β-agonist modulator compounds that can bias β2AR signaling such that the beneficial Gs pathway is optimized and the detrimental β-arrestin pathway is minimized. To test this central hypothesis we will employ murine in vivo and in vitro cell-specific genetic deletion and gain-of-function models to test the efficacy of newly discovered and existing β2AR ligands to bias signaling and reduce the asthma phenotype. In a translational aim we will harvest airway epithelial cells from severe asthmatics and determine if β2AR signaling bias is effective in reducing inflammatory endpoints.

Collectively, these studies will significantly advance the fields of asthma biology and asthma pharmacology by identifying a fundamental pathogenic signaling mechanism involved in allergic lung inflammation, and by characterizing the optimal β2AR ligands used to manage asthmatics. 

This project is relevant to public health because it has a high likelihood of finding new, or improving current, asthma medications. Furthermore, the results could alter our understanding of β2AR function in asthma at a paradigm-shifting level. Finally, the signaling pathways and ligands we reveal in this project could be highly applicable to drug discovery for many other diseases.