Walker Submits NIH R01 Grant Application on Asthma

Walker Submits NIH R01 Grant Application on Asthma

Kudos to Julia Walker, professor, and her entire team for the submission of their R01 application entitled: "Optimizing Beta-Adrenoceptor Signaling Bias in Asthma." This proposal requests funds for a 5 year period with a start date of July 1, 2020.

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 current asthma treatments. Our recent published and unpublished studies provide compelling insight into why β-agonists are problematic while offering a solution to their clinical application. Our overarching hypothesis is that β2AR agonism plays a permissive role in the development of allergic lung inflammation and associated airway hyperresponsiveness (AHR) through activation of a pro-inflammatory β-arrestin2-dependent signaling pathway. This pathway is in contrast to the bronchoprotective β2AR signaling mediated by Gs proteins.

Our most recent studies point to airway epithelia as the prime candidate through which β-arrestin2 regulates allergen-induced inflammation, and we now propose novel models to clarify the mechanisms by which such regulation occurs. We will employ a comprehensive set of systems, including primary and immortalized, human and murine cell cultures, and in vivo models, to test the central hypothesis that β2AR-signaling via β-arrestin2 in airway epithelia is critical to the allergen-induced asthma phenotype. We have also created novel biased β2AR ligands or modulators that antagonize β-arrestin2 signaling while enabling Gs protein signaling, and hypothesize they will have superior efficacy in the treatment of asthma.

Aim 1 will employ genetic and novel β2AR ligand strategies enabling cell-specific β-arrestin2 or Gs gene ablation or signal biasing to establish the requirement and sufficiency of β2AR agonism in airway epithelial cells in mediating allergic lung inflammation, mucin production, and AHR. Aim 2 will employ similar genetic and novel β2AR ligand approaches to identify G protein- dependent and -independent regulation of cytokine and mucous production in cultured murine epithelial cultures. Aim 3 will identify G protein-dependent and -independent mechanisms of β2AR regulation of cytokine and mucous production in human airway epithelial cultures derived from phenotyped non-asthmatic and severe asthmatic subjects. Finally, in Aim 4, we will employ a novel “gain of function” model to gather mechanistic insight into biased β2AR signaling and function.

Collectively, these studies will significantly advance the fields of asthma biology, G protein-coupled receptor 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.

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