ABSTRACT: This R03 proposal has been prepared in response to RFA-RM-21-012 entitled “Pilot Projects Investigating Understudied G Protein-Coupled Receptors, Ion Channels, and Protein Kinases.” Our research will focus on human bitter taste receptors (TAS2Rs) in the G protein-coupled receptor family, whose expression is detected in the respiratory system. These receptors have been designated as eligible proteins open for study by NIH’s Illuminating the Druggable Genome (IDG) Program associated with this RFA, and their roles in bitter tastant/TAS2R-agonist-based therapies for asthma need to be elucidated. Asthma is a major public health challenge and the most common chronic disease in the pediatric population. In the United States, over 25 million people, including 8.4% of all children, are currently suffering from asthma with an estimated annual cost of ~$82 billion. At present, the main treatment strategies are based on β2-adrenergic receptor agonists, corticosteroids, and monoclonal antibodies. However, questions remain about the long-term efficacy and safety of these approaches. In addition, there is still no effective treatment for progressive airway remodeling, which plays a critical role in asthma-related deaths. All these factors provide a strong impetus for investigations of bitter tastants/TAS2R agonists for treating asthma because it has been recently shown that these agents have a superior efficacy for asthma treatment in animal models, in which data suggest that these agonists can potentially overcome critical deficiencies associated with current therapeutics such as those related to progressive airway remodeling. The long-term goal of our efforts is to further understand TAS2Rs mechanistically in terms of the physiological, pathological, and therapeutic processes associated with asthma treatment. In this pilot project, we propose to test the hypothesis that bitter taste receptors play an essential role in bitter tastant/TAS2R-agonist- based therapeutic strategies for asthma. Accordingly, we will engineer mouse mutants deficient for Tas2r genes or carrying a single Tas2r gene by using highly efficient CRISPR-based technology. We will also compare the outcomes of bitter tastants/TAS2R-agonist-based treatment of asthma and associated signaling in homozygous mutants and wild-type littermates. These experiments will help us to better understand the molecular mechanisms underlying bitter tastant/TAS2R-agonist-based therapies for asthma. Our study will also reveal if TAS2Rs are essential for the survival of mice. Lastly, the genetic resources developed during this study will be powerful tools for unraveling the physiological, pathological, and therapeutic roles of TAS2Rs related to other medical conditions, such as obesity, diabetes, and preterm labor.

PROJECT NARRATIVE: Recent data show that bitter tastant-based treatments can significantly alleviate the clinical features associated with asthma in animal models. In this project, we will engineer mouse models carrying mutant alleles of bitter taste receptor genes and test the hypothesis that activation of bitter taste receptors is essential in bitter tastant-based therapies. Attainment of our objectives will help us to gain new insight into the physiological functions of these druggable targets, fully unravel the therapeutic mechanism, and enhance our ability to develop more effective treatment strategies for the most challenging clinical features of refractory asthma, including those associated with progressive airway remodeling.