The Role of PPARgamma in Th2 cells and Obesity-Associated Asthma.

PPARgamma 在 Th2 细胞和肥胖相关哮喘中的作用。

• 批准号: 10058176
• 负责人: Sagar Pradeep Bapat
• 金额: $ 11.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058176
• 关键词: Adipocytes; Adipose tissue; Adrenal Cortex Hormones; Advisory Committees; Affect; Agonist; Asthma; Atopic Dermatitis; Award; Biology; Biometry; Blood Cells; Bronchoalveolar Lavage Fluid; California; Cardiovascular Diseases; Cellular biology; Chronic; Clinical; Clinical Research; Data; Data Science; Data Set; Development; Development Plans; Disease Management; Doctor of Medicine; Doctor of Philosophy; Effector Cell; Elements; Environment; FDA approved; Foundations; Functional disorder; Gene Expression; Gene Targeting; Genes; Genomic approach; Goals; Health; Helper-Inducer T-Lymphocyte; High Fat Diet; Hospitalization; Human; Immune response; Immunity; Immunology; Immunosuppressive Agents; In Vitro; Insulin Resistance; Intention; Interleukin-4; Investigation; Kidney Diseases; Lipids; Liver; Liver diseases; Lung; Maps; Measures; Mentorship; Metabolic; Molecular; Mus; Muscle; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Obese Mice; Obesity; PPAR gamma; Pathogenesis; Pathologist; Patients; Pharmaceutical Preparations; Physicians; Physiological; Public Health; Pyroglyphidae; Quality of life; Refractory; Research; Research Ethics; Risk Factors; Role; San Francisco; Scientist; Severities; Severity of illness; Skin; Source; T-Cell Development; T-Lymphocyte; Testing; Th2 Cells; Thiazolidinediones; Thinness; Training; Transcriptional Regulation; United States; Universities; Work; asthma model; asthmatic patient; base; cancer type; career development; clinically relevant; comorbidity; cost; cytokine; epidemiology study; functional genomics; gene function; in vivo; lipid biosynthesis; loss of function; member; multidisciplinary; novel therapeutic intervention; obesity development; pre-clinical; programs; response; restraint; sensor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Obesity is a major public health challenge in the United States and worldwide. The chronic complications and comorbidities from obesity represent one of the greatest challenges to human health. Recent clinical and epidemiological studies have demonstrated the development of asthma to be strongly associated with obesity. In fact, obese asthma patients tend to have increased severity of disease and respond poorly to conventional asthma medications, including corticosteroids. Altogether these observations suggest that obesity-associated asthma may have a distinct molecular pathophysiology compared to other forms of asthma. As such, my long-term research goal is to elucidate the molecular, cellular, and physiological mechanisms that potentiate obesity-associated asthma in order to identify novel therapeutic approaches for the management of this disease. The objective of this proposal is to determine the role of the nuclear hormone receptor PPARg (peroxisome proliferator activated receptor gamma) in TH2 cell effector function and obesity- associated asthma. In previous work, I have discovered that PPARg functions as a brake on TH2 effector function and that the restraint is abolished in the obese state. My central hypothesis is that obesity dysregulates PPARg in TH2 cells to potentiate TH2 cell-driven asthma. I will test this hypothesis using two specific aims. In Aim 1, I will map the PPARg cistrome in TH2 cells isolated directly from the lungs of lean and obese mice being challenged with experimental asthma to determine if and how the direct and indirect gene targets of PPARg change with changes in metabolic state. I will also map the PPARg cistrome in in vitro differentiated human TH2 cells. In Aim 2, using lean and obese mice whose T cells are sufficient or deficient in PPARg, I will determine the role of T cell-specific PPARg in the development of obesity-associated asthma. I am an M.D., Ph.D.-trained clinical pathologist working as a UCSF StARR Scholar at the University of California, San Francisco. I am applying for the K38 Award to support my goal of becoming an independent physician scientist. UCSF's exceptional training environment, especially in the fields of immunology, obesity, and asthma, will support my efforts in this regard. Critical elements of my career development plan include mentorship by Dr. Alexander Marson, an expert in utilizing functional genomics approaches to investigate T cell biology in mouse and human; co-mentorship by Dr. Richard Locksley, an expert in Type 2 immunity, helper T cell development, and in vivo immunology; co-mentorship by Dr. John Fahy, an expert in translational asthma research with expertise in obesity-associated asthma; guidance by a multidisciplinary advisory committee which include senior physician-scientists; coursework in data science (R programing), biostatistics, and research ethics; and professional development activities. Taken together, this career development plan will establish a strong foundation on which to build my growing expertise on how obesity alters immune responses.

项目摘要/摘要 肥胖是美国和世界范围内的一项重大公共卫生挑战。慢性并发症 肥胖带来的并存是人类健康面临的最大挑战之一。最近的临床和 流行病学研究表明，哮喘的发展与肥胖密切相关。 事实上，肥胖的哮喘患者往往疾病严重程度增加，对常规治疗的反应较差。 哮喘药物，包括皮质类固醇。总之，这些观察表明，与肥胖相关的 与其他形式的哮喘相比，哮喘可能具有独特的分子病理生理学。 因此，我的长期研究目标是阐明分子、细胞和生理上的 强化肥胖相关哮喘的机制，以确定治疗肥胖相关哮喘的新方法 这种疾病的管理。这项建议的目的是确定核激素的作用 PPARg受体在TH2细胞效应器功能和肥胖中的作用 相关性哮喘。在以前的工作中，我发现PPARg在TH2效应器功能上起到刹车的作用 而在肥胖状态下，这种限制被取消了。我的中心假设是肥胖使PPARg在 Th2细胞增强TH2细胞驱动的哮喘。我将用两个具体目标来检验这一假设。在《目标1》中，我将 直接从瘦肥胖小鼠肺部分离的TH2细胞中PPARg序列的图谱 用实验性哮喘来确定PPARg的直接和间接基因靶点是否以及如何随着 代谢状态的变化。我还将在体外分化的人类TH2细胞中定位PPARg序列。在AIM 2，使用T细胞PPARg充足或不足的瘦小鼠和肥胖小鼠，我将确定T细胞的作用 细胞特异性PPARg在肥胖相关哮喘发生中的作用 我是一名医学博士和博士学位的临床病理学家，在加州大学旧金山分校担任斯塔尔学者。 加利福尼亚州，旧金山。我正在申请K38奖，以支持我成为一名独立人士的目标 内科科学家。加州大学旧金山分校卓越的培训环境，特别是在免疫学、肥胖症和 哮喘，将支持我在这方面的努力。我职业发展计划的关键要素包括指导 亚历山大·马森博士是一位利用功能基因组学方法研究T细胞生物学的专家 小鼠和人类；由2型免疫专家理查德·洛克斯利博士共同指导，辅助T细胞 发育和体内免疫学；转化性哮喘专家约翰·法希博士的共同指导 在与肥胖相关的哮喘方面具有专业知识的研究；由多学科咨询委员会指导，该委员会 包括资深内科科学家；数据科学(R编程)、生物统计学和研究课程 道德操守；以及职业发展活动。综上所述，这项职业发展计划将建立 在此基础上，我在肥胖如何改变免疫反应方面积累了越来越多的专业知识。