Metabolic dysregulation and therapeutic intervention in asthma

Research Inst Nationwide Children'S Hosp, Columbus OH

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Abstract

? DESCRIPTION (provided by applicant): The T-helper type 2 (TH2) cells account for the pathogenesis of a major subset of asthma. Recent studies from others and us have shown that T cell metabolic pathways are tightly and ubiquitously linked with T cell immune functions. This proposal focuses on the metabolic regulation of TH2 cell pathogenesis in asthma. In our recent study on T cell metabolic reprogramming, the proto-oncogene, Myc, was identified as one of the key nodes coordinately regulating T cell metabolism and immune responses. Our preliminary studies further suggested that Myc is required for maintaining the metabolic activities during TH2 differentiation and T cell specific deletion of Myc blocks pathogenic TH2 development in a mouse model of asthma. We hypothesize that the Myc-mediated metabolic program contributes to the development of pathogenic TH2 cells and represents a novel therapeutic target in asthma. We propose to (1) determine the metabolic requirement and dependency of TH2 cell and assess the role of Myc in metabolic maintenance during TH2 cell differentiation; (2) assess Myc-dependent metabolic reprogramming as a novel therapeutic target in a mouse model of asthma. Our proposed studies will provide novel opportunities to understand and manipulate TH2 cell responses during asthma pathogenesis. Notably, several pharmacological agents proposed in this study have been either recently approved by FDA or entered clinical trials in several cancer and autoimmune diseases. We therefore expect that the positive preclinical data in our animal models can be rapidly translated into potential clinical progress in treating asthma patients.