Metabolic dysregulation and therapeutic intervention in asthma

 描述（由申请人提供）：辅助性T细胞2型（TH 2）细胞是哮喘的主要发病机制。近年来的研究表明，T细胞代谢途径与T细胞免疫功能密切相关。该建议的重点是TH 2细胞在哮喘发病机制中的代谢调节。在我们最近对T细胞代谢重编程的研究中，原癌基因Myc被确定为协调调节T细胞代谢和免疫应答的关键“节点”之一。我们的初步研究进一步表明，Myc是维持TH 2分化过程中的代谢活性所必需的，并且Myc的T细胞特异性缺失阻断了哮喘小鼠模型中致病性TH 2的发展。我们假设Myc介导的代谢程序有助于致病性TH 2细胞的发展，并代表了哮喘的新治疗靶点。本研究拟（1）确定TH 2细胞的代谢需求和依赖性，并评估Myc在TH 2细胞分化过程中代谢维持的作用;（2）评估Myc依赖的代谢重编程作为哮喘小鼠模型中的新治疗靶点。我们提出的研究将提供新的机会，了解和操纵哮喘发病过程中的TH 2细胞反应。值得注意的是，本研究中提出的几种药理学药物最近已被FDA批准或进入几种癌症和自身免疫性疾病的临床试验。因此，我们希望我们的动物模型中的积极临床前数据可以迅速转化为治疗哮喘患者的潜在临床进展。

 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.