Regulation and function of allergic immune cells in visceral adipose tissue

描述（由申请人提供）：Ari Molofsky博士是K08指导临床科学家研究职业发展奖的候选人。Molofsky博士是MSTP毕业生和血液病理学家，目前担任加州大学旧金山分校的临床讲师。这份职业发展建议有两个主要目标。首先，Molofsky博士概述了一个5年的职业发展计划，其中包括Richard Locksley博士的指导，一个提供科学和职业建议的多学科委员会，教学课程，促进科学发展和合作的会议，以及实验室管理和专业技能的研讨会。其次，莫洛夫斯基博士概述了一项为期5年的研究策略，旨在研究与脂肪组织中过敏免疫相关的基本问题。全世界肥胖和2型糖尿病的患病率急剧上升，导致了大量的发病率和死亡率。肥胖促进脂肪组织炎症，是胰岛素抵抗发展为糖尿病的早期事件。相反，许多与过敏、抗蠕虫免疫相关的免疫细胞存在于瘦脂肪组织中，在肥胖诱导的胰岛素抵抗和糖尿病模型中具有保护作用。莫洛夫斯基博士的长期目标是阐明协调调节，细胞相互作用，以及

DESCRIPTION (provided by applicant): Dr. Ari Molofsky is the candidate applying for the K08 Mentored Clinical Scientist Research Career Development Award. Dr. Molofsky is an MSTP graduate and a Hematopathologist, currently serving as a Clinical Instructor at the University of California San Francisco. This career development proposal has two primary goals. First, Dr. Molofsky outlines a 5-year career development plan that includes mentorship by Dr. Richard Locksley, a multidisciplinary committee structured to provide scientific and career advice, didactic coursework, meetings to promote scientific growth and collaborations, as well as workshops on laboratory management and professional skills. Second, Dr. Molofsky outlines a 5-year research strategy to examine fundamental questions related to allergic immunity in adipose tissue. The worldwide prevalence of obesity and type 2 diabetes has risen dramatically, leading to significant morbidity and mortality. Obesity promotes adipose tissue inflammation and is an early event in the development of insulin resistance and progression to frank diabetes. In contrast, a number of immune cells related to allergic, anti-helminth immunity reside in lean adipose tissue and are protective in models of obesity induced insulin resistance and diabetes. Dr. Molofsky's long-term goal is to elucidate the coordinate regulation, cellular interactions, and individual contributions to metabolic homeostasis of allergic immune cells in metabolic health and disease. The objective of this application is to understand the signals that promote the function of adipose tissue lymphocytes, including innate lymphoid type 2 cells (ILC2), adaptive Th2, and regulatory T cells (Treg), as well as the individual contributions to metabolic homeostasis of each cell type in models of obesity and insulin resistance. The central hypothesis of this proposal is that epithelial cytokines, including IL-33, are actively produced in adipose tissue and coordinately regulate ILC2, Th2, and Treg cells, each of which uniquely contribute to metabolic outcomes. Dr. Molofsky will achieve the objective of this proposal by pursuing three specific aims. In Aim 1, Dr. Molofsky will test the hypothesis that combinations of epithelial cytokines, including IL-33 and TSLP, promote adipose tissue ILC2 function and cytokine secretion. Using unique ILC2 deficient animals, the precise metabolic impact of ILC2 will be assessed. In Aim 2, Dr. Molofsky will address the regulation and metabolic contributions of adaptive Th2 cells in adipose tissue, testing the hypothesis that Th2 cells provide a mechanism to increase production of allergic immunity-related cytokines with age and after helminth infection. In Aim 3, Dr. Molofsky will test the hypothesis that the epithelial cytokine IL 33, along with unknown ILC2 factor(s), coordinately regulate and support adipose tissue Tregs, which are protective in models of obesity-induced insulin resistance. This project is relevant to diabetes research and the mission of the NIH and NIDDK because it has the potential to reveal novel cellular and molecular targets related to allergic immunity that are protective against obesity and the development of diabetes.