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.
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.
|Lu, Yun; Liu, Huanrong; Bi, Yujing et al. (2017) Glucocorticoid receptor promotes the function of myeloid-derived suppressor cells by suppressing HIF1?-dependent glycolysis. Cell Mol Immunol :|
|Shen, Yuqing; Vignali, Paolo; Wang, Ruoning (2017) Rapid Profiling Cell Cycle by Flow Cytometry Using Concurrent Staining of DNA and Mitotic Markers. Bio Protoc 7:|
|Gnanaprakasam, J N Rashida; Wang, Ruoning (2017) MYC in Regulating Immunity: Metabolism and Beyond. Genes (Basel) 8:|
|Gnanaprakasam, J N Rashida; Sherman, John William; Wang, Ruoning (2017) MYC and HIF in shaping immune response and immune metabolism. Cytokine Growth Factor Rev 35:63-70|
|Xiao, Yun; Tang, Juan; Guo, Hui et al. (2016) Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. Nat Med 22:906-14|
|Liu, Lingling; Lu, Yun; Martinez, Jennifer et al. (2016) Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1?-dependent. Proc Natl Acad Sci U S A 113:1564-9|
|Slack, Maria; Wang, Tingting; Wang, Ruoning (2015) T cell metabolic reprogramming and plasticity. Mol Immunol 68:507-12|
|Liu, Guangwei; Bi, Yujing; Xue, Lixiang et al. (2015) Dendritic cell SIRT1-HIF1? axis programs the differentiation of CD4+ T cells through IL-12 and TGF-?1. Proc Natl Acad Sci U S A 112:E957-65|
|Xiao, Yun; Qiao, Guilin; Tang, Juan et al. (2015) Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation. J Immunol 195:4218-27|