A role for pharmaceutical control of protease-activated receptor-2 for the treatment of asthma

PROJECT ABSTRACT Asthma is a heterogenous disease that impacts ~10% of the US population. It presents as a syndrome of non- specific airway hyperresponsiveness, inflammation and intermittent respiratory symptoms. Even though more than half of patients receiving standard asthma medication remain uncontrolled, mainstay treatments have been largely unchanged for several decades. While the introduction of the asthma-specific biologics in the last several years has improved asthma for some, those treatments are extremely costly and are typically reserved for the most severe of patients. For most asthma patients, responses are mediated by environmental allergens which frequently possess potent protease activity. These allergen proteases provoke an increased allergen response, in part by the direct activation of protease-activated receptor-2 (PAR2). PAR2 is a newly established target for development of novel analgesics and therapeutics for inflammatory diseases, including asthma. We have developed novel antagonists to PAR2 that in preliminary experiments using pre-clinical models have proven to be effective in inhibiting or reducing the detrimental physiological changes associated with allergen-induce asthma. Our central hypothesis for this application is: Small molecule pharmacological control of airway epithelial and/or nociceptor PAR2 signaling provides a novel strategy for asthma protection that can be demonstrated in vivo. We propose 3 specific aims, in which we will use a combination of in vitro and in vivo approaches to uncover a mechanistic understanding for the roles for epithelial- and neuronal-expressed PAR2 in allergic asthma. These studies will specify pharmacological impact of PAR2 modulation on airway epithelial cells and sensory neurons in vitro and in pre-clinical asthma models with human validation and will provide mechanistic understanding and cellular targeting for development of novel asthma drugs for clinical trials.