Regulation and function of allergic immune cells in visceral adipose tissue

简介(申请人提供)：阿里·莫洛夫斯基博士是K08临床科学家导师研究职业发展奖的候选人。莫洛夫斯基博士毕业于MSTP，是一名血液病理学家，目前在加州大学旧金山分校担任临床讲师。这份职业发展提案有两个主要目标。首先，莫洛夫斯基博士概述了一项为期5年的职业发展计划，其中包括理查德·洛克斯利博士的指导，这是一个多学科委员会，旨在提供科学和职业建议、教学课程、促进科学增长和合作的会议，以及关于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年的研究战略，旨在研究与脂肪组织过敏性免疫相关的基本问题。肥胖症和2型糖尿病在全球范围内的患病率急剧上升，导致严重的发病率和死亡率。肥胖促进脂肪组织炎症，是胰岛素抵抗和糖尿病进展的早期事件。相反，一些与过敏、抗蠕虫免疫相关的免疫细胞驻留在瘦脂肪组织中，在肥胖导致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、细胞相互作用和 个体对代谢健康和疾病中过敏免疫细胞代谢动态平衡的贡献。这项应用的目的是了解促进脂肪组织淋巴细胞功能的信号，包括先天性淋巴样细胞2型细胞(ILC2)、适应性Th2细胞和调节性T细胞(Treg)，以及在肥胖和胰岛素抵抗模型中每种细胞类型对代谢稳态的个体贡献。这一建议的中心假设是，包括IL-33在内的上皮细胞因子在 脂肪组织和协调调节ILC2、Th2和Treg细胞，其中每一个都对代谢结果有独特的贡献。莫洛夫斯基博士将通过追求三个具体目标来实现这项提案的目标。在目标1中，莫洛夫斯基博士将检验这一假设，即包括IL-33和TSLP在内的上皮性细胞因子组合可以促进脂肪组织ILC2的功能和细胞因子的分泌。使用独特的ILC2缺陷动物，将评估ILC2的精确代谢影响。在目标2中，莫洛夫斯基博士将研究适应性Th2细胞在脂肪组织中的调节和代谢作用，验证Th2细胞提供了一种机制，随着年龄和蠕虫感染后增加过敏免疫相关细胞因子的产生的假说。在目标3中，莫洛夫斯基博士将检验上皮性细胞因子IL 33与未知的ILC2因子(S)协同调节和支持脂肪组织Tregs，在肥胖诱导的胰岛素抵抗模型中具有保护作用。该项目与糖尿病研究以及NIH和NIDDK的使命相关，因为它有可能揭示与过敏性免疫相关的新的细胞和分子靶点，这些靶点可以预防肥胖和糖尿病的发生。

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.