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

项目总结/摘要 肥胖是美国和世界范围内的一个重大公共卫生挑战。慢性并发症 肥胖症的并发症是人类健康面临的最大挑战之一。最近的临床和 流行病学研究已经证明哮喘的发展与肥胖密切相关。 事实上，肥胖哮喘患者往往具有增加的疾病严重性，并且对常规治疗反应差。 哮喘药物，包括皮质类固醇。总之，这些观察结果表明，肥胖相关的 与其它形式的哮喘相比，哮喘可能具有不同的分子病理生理学。 因此，我的长期研究目标是阐明分子，细胞和生理 增强肥胖相关哮喘的机制，以确定新的治疗方法， 管理这种疾病。这项建议的目的是确定核激素的作用 受体PPARg（过氧化物酶体增殖物激活受体γ）在TH 2细胞效应功能和肥胖中的作用- 相关哮喘在以前的工作中，我发现PPARg的功能是抑制TH 2效应器功能 并且在肥胖状态下该约束被取消。我的中心假设是肥胖症导致PPARg失调， TH 2细胞，以增强TH 2细胞驱动的哮喘。我将使用两个具体目标来检验这个假设。在目标1中，我将 绘制直接从受攻击的瘦小鼠和肥胖小鼠的肺中分离的TH 2细胞中的PPARg顺式组 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TH 2细胞中绘制PPARg顺式组。在Aim中 2，使用T细胞充足或缺乏PPARg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在肥胖相关性哮喘发生中的作用 我是医学博士，博士学位-作为UCSF StARR学者，他在加州大学伯克利分校接受过临床病理学家培训， 加州，旧金山弗朗西斯科。我正在申请K38奖，以支持我成为一个独立的目标 医学科学家加州大学旧金山分校的特殊培训环境，特别是在免疫学，肥胖， 哮喘，将支持我在这方面的努力。我的职业发展计划的关键要素包括导师制 作者是亚历山大·马森博士，他是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、辅助性T细胞和免疫学专家Richard Locksley博士共同指导 发育和体内免疫学;由转化型哮喘专家John Fahy博士共同指导 肥胖相关哮喘的专业研究;由多学科咨询委员会指导， 包括高级医生-科学家;数据科学（R编程）、生物统计学和研究课程 道德操守;专业发展活动。总体而言，这一职业发展计划将建立一个 这是我在肥胖如何改变免疫反应方面不断增长的专业知识的坚实基础。

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.