Regulation of Adipose Tissue Inflammation and Insulin Resistance by T Cell Subset

描述（由申请人提供）：脂肪组织的慢性炎症现在被公认为是导致胰岛素抵抗和最终2型糖尿病发展的关键因素。然而，关于不同T细胞亚群在加重或调节肥胖诱导的脂肪组织炎症中的作用知之甚少。我建议使用小鼠遗传学来阐明特定T细胞亚群在脂肪组织炎症中的作用。此外，我将使用小鼠遗传学和T细胞的体外培养物来确定Foxo转录因子的调节改变如何影响肥胖症中的T细胞功能，Foxo转录因子整合了有关营养物质，生长因子和压力的丰富信息，以调节包括T细胞存活，分化和功能在内的广泛反应。我的长期目标是了解肥胖如何影响T细胞，从而了解T细胞如何调节脂肪组织炎症、胰岛素抵抗和2型糖尿病的发展。在本申请中，我提出1）研究T细胞亚群在高脂肪饮食诱导的胰岛素抵抗和葡萄糖耐受不良中的作用，2）研究T调节细胞向脂肪组织的归巢，以及3）确定肥胖如何影响免疫细胞中的Foxo转录因子调节以及Foxo转录因子的缺失如何影响胰岛素抵抗和葡萄糖耐受不良。本申请中提出的研究将作为我作为独立研究者进行研究的基础。这个K 01资助申请将特别有助于我获得独立研究适应性免疫系统在脂肪组织炎症和胰岛素抵抗中的作用，因为它将使我有保护的时间开始将我的传统免疫学训练应用于肥胖/脂肪组织/胰岛素抵抗研究。此外，为了更好地为独立调查员的职业生涯做好准备，我制定了一个职业发展计划。作为此应用程序的一部分，我建议获得炎症研究，微阵列分析，显微镜和克隆的额外培训;并参加旨在为我的教师生涯做准备的课程和研讨会，包括：公开演讲，赠款写作，粉笔会谈和实验室管理。在我看来，我已经展示了我作为一名独立研究者取得成功的潜力，因为我作为博士后研究员在指导其他科学家和团队在圣地亚哥州立大学教授一门课时，作为NIH资助的IRACDA计划的一部分，我一直在富有成效地发表文章。最后，加州圣地亚哥大学的环境让我有机会成为一名研究人员，我相信这将继续让我茁壮成长，最终成为一名独立的研究人员。

DESCRIPTION (provided by applicant): Chronic inflammation of adipose tissue is now well recognized to be a key factor leading to the development of insulin resistance and eventually type 2 diabetes. However, little is known about the role of different T cell subsets in exacerbating or regulating adipose tissue inflammation induced by obesity. I propose to use mouse genetics to unravel the role of specific T cell subsets in adipose tissue inflammation. Furthermore, I will use mouse genetics and in vitro cultures of T cells to determine how altered regulation of Foxo transcription factors, factor that integrate information concerning the abundance of nutrients, growth factors and stress to regulate a wide range of responses including T cell survival, differentiation and function, affects T cell function in obesity. My lon-term goal is to understand how obesity affects T cells and thus how T cells regulate the development of adipose tissue inflammation, insulin resistance, and type 2 diabetes. In this application I propose to 1) investigate the role of T cell subsets in high fat diet -induced insuli resistance and glucose intolerance, 2) investigate the homing of T regulatory cells to the adipose tissue and, 3) Determine how obesity affects Foxo transcription factors regulation in immune cells and how loss of Foxo transcription factors affects insulin resistance and glucose intolerance. The research proposed in this application will serve as a foundation for my research as an independent investigator. This K01 grant application will be particularly helpful for me to gain independence studying the role of the adaptive immune system in adipose tissue inflammation and insulin resistance, as it will allow me protected time to begin applying my traditional immunology training to the obesity/adipose tissue/insulin resistance research. Additionally, in order to better prepare myself for a career as independent investigator I have developed a career development plan. As part of this application I propose to gain additional training in inflammation research, microarray analysis, microscopy, and cloning; and to attend classes and seminars designed to prepare me for a faculty career including: public speaking, grant writing, chalk talks, and lab management. In my opinion I have already shown my potential to succeed as an independent investigator as I have been productive publishing as a postdoctoral fellow while mentoring other scientists and team teaching a class at San Diego State University as part of the NIH-funded IRACDA program. Finally, it is environment at the University of California San Diego, which has allowed me the opportunities to develop as a researcher, and that I believe will continue to allow me to thrive and grow to eventually become and independent investigator.