Metabolic dysregulation and therapeutic intervention in asthma

哮喘的代谢失调和治疗干预

基本信息

批准号：
8872327
负责人：
Ruoning Wang
金额：
$ 20.15万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-23 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8872327
关键词：
Accounting Achievement Acute Animal Model Area Asthma Autoimmune Diseases Bioenergetics Bromodomain Cell Differentiation process Cell Surface Receptors Cell division Cells Chromatin Chronic Citric Acid Cycle Clinical Clinical Trials Complex Data Dependency Development Disease Progression Environment Enzymes Event FDA approved Fumarates Gene Expression Profile Genetic Glycolysis Immune Immune System Diseases Immune response In Vitro Inflammatory Inflammatory Response Link Lung diseases Lymphocyte Maintenance Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Multiple Sclerosis Mus Oral Outcome Ovalbumin Pathogenesis Pathway interactions Phase Process Proliferating Property Proteins Proto-Oncogenes Psoriasis Refractory Regulation Research Role Severities Signal Transduction Staging Syndrome T cell differentiation T-Lymphocyte Th2 Cells Therapeutic Therapeutic Intervention Tissues Translating aerobic glycolysis airway hyperresponsiveness airway inflammation asthmatic asthmatic patient c-myc Genes cytokine fatty acid oxidation immune function in vivo inhibitor/antagonist meetings mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics pathogen pre-clinical programs public health relevance pulmonary function receptor-mediated signaling reconstitution response therapeutic target

项目摘要

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.

描述（由申请人提供）：2 型辅助 T (TH2) 细胞是哮喘主要亚型的发病机制。其他人和我们最近的研究表明，T 细胞代谢途径与 T 细胞免疫密切相关。该提案重点关注哮喘中 TH2 细胞发病机制的代谢调节。在我们最近的 T 细胞代谢重编程研究中，原癌基因 Myc 被确定为关键“节点”之一。我们的初步研究进一步表明，Myc 是维持 TH2 分化过程中代谢活动所必需的，并且 Myc 的 T 细胞特异性删除可阻止哮喘小鼠模型中致病性 TH2 的发育。介导的代谢程序有助于致病性 TH2 细胞的发育，并代表哮喘的新治疗靶点。我们建议（1）确定 TH2 细胞的代谢需求和依赖性，并评估 Myc 在 TH2 细胞分化过程中代谢维持的作用； (2) 评估 Myc 依赖性代谢重编程作为哮喘小鼠模型的新治疗靶点，我们提出的研究将为理解和操纵哮喘发病机制期间的 TH2 细胞反应提供新的机会。最近获得 FDA 批准或进入多种癌症和自身免疫性疾病的临床试验，因此我们期望我们的动物模型中积极的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。