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.

Public Health Relevance

This project explores how metabolism is controlled in asthma and impact on pathogenesis, at the level of precise cellular mechanism and amenable to pharmacologic manipulation. This is an emerging new research area that will enable us to develop novel therapeutic intervention of targeting metabolic pathways for inflammatory and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI117547-01
Application #
8872327
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Davidson, Wendy F
Project Start
2015-06-23
Project End
2017-05-31
Budget Start
2015-06-23
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
$201,500
Indirect Cost
$49,500
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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