? OVERALL PROGRAM More than 25 million Americans suffer from asthma, and nearly half do not have their asthma under control. Standard treatment is limited, and a stepped care approach is applied uniformly to all patients regardless of the underlying mechanisms of asthma. Our Asthma Inflammation Research [AIR] Program aims to uncover fundamental mechanisms of asthma and identify biomarkers of those pathways that will define mechanistic endotypes of asthma in order to target therapies in a precision medicine approach of care. In Cycle I of the TPPG, we uncovered new mechanisms of airway inflammation and hyper-reactivity. In Cycle II, we apply the fundamental discoveries to precisely target pathways for bronchodilation (Project 3) and inflammation (Projects 1 and 2). Based on findings that oxidative metabolism mechanistically contributes to asthma, Project 1 investigates whether diet can modulate inflammatory responses, gene expression, and airway reactivity. Metabolic endotypes will be elucidated, and a specific biomarker of eosinophil activation, bromotytrosine (BrTyr) is tested in asthma control and biologic-based therapies of asthma. Project 2 has identified T-Helper 17 [TH17] pathways in origins of severe asthma. In Cycle II, Project 2 determines if, and how, TH17 cytokines drive pathologic inflammation, and uses the information to develop serum biomarkers of this endotype, and small molecule inhibitors and peptidomimetics of IL-17A for treatment of asthma. Project 3 shows that high levels of nitric oxide (NO) and oxidants in asthmatic airways damage soluble guanylate cyclase (sGC), making it NO-insensitive and diminishing the NO-sGC pathway from acting in bronchodilation. In Cycle II, Project 3 develops bronchodilator drug response profiling to identify sGC endotypes, and tests sGC activators and stimulators in asthma preclinical models to support a new indication for sGC drugs as bronchodilators. The projects benefit from model systems and efficiencies of cores, including a new Technology Development and Commercialization Core B, and innovative murine models of asthma and airflow imaging in Core C. Partnerships with Pharmaceutical & Biotechnology, Nutrition, Health & Wellness companies, and strategic leveraging of Cleveland-based NHLBI National Centers for Accelerating Innovation (NCAI-CC) and the NSF Innovations Corps at Cleveland Clinic ensure that our discoveries will be implemented over the next 5 years. Altogether, the program provides an unparalleled opportunity for efficient progression of personalized asthma care products to the marketplace for patients.
? OVERALL PROGRAM The Asthma Inflammation Research Program aims to uncover the underlying pathways that lead to asthma and develop biomarkers of the pathways in order to define endotypes of disease and target therapies specific to the causal pathways in a precision medicine approach of care.
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