Regulation and function of allergic immune cells in visceral adipose tissue

内脏脂肪组织中过敏性免疫细胞的调节和功能

基本信息

批准号：
9020959
负责人：
Ari B Molofsky
金额：
$ 15.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020959
关键词：
Address Adipose tissue Age Aging Allergic Allergic inflammation Animals Anti-Allergic Agents Anti-Inflammatory Agents Anti-inflammatory CD4 Positive T Lymphocytes California Cells Clinical Collaborations Data Development Development Plans Diabetes Mellitus Diet Disease Educational workshop Endocrine Glands Energy Intake Epithelial Event Future GATA3 gene Goals Growth Health Helminths Helper-Inducer T-Lymphocyte Homeostasis Human Hypersensitivity Immune Immune response Immunity Individual Infection Inflammation Inflammatory Inflammatory Response Insulin Resistance Interleukin-13 Interleukin-5 K-Series Research Career Programs Knowledge Laboratories LoxP-flanked allele Lymphocyte Lymphoid Maintenance Mediating Mentors Mentorship Metabolic Mission Modeling Molecular Molecular Target Morbidity - disease rate Mus National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Prevalence Production Reagent Regulation Regulatory T-Lymphocyte Reporter Research Resistance development Resources Role San Francisco Scientist Signal Pathway Signal Transduction Source Structure T-Lymphocyte TSLP gene Testing Th2 Cells Therapeutic Tissues United States National Institutes of Health Universities Visceral aged career career development cell growth regulation cell type cellular targeting cytokine eosinophil in vivo instructor insulin sensitivity macrophage meetings mortality multidisciplinary novel programs receptor response skills targeted treatment tool

项目摘要

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.

描述（由申请人提供）：Ari Molofsky博士是申请K08指导的临床科学家研究职业发展奖的候选人。 Molofsky博士是MSTP毕业生和血管病医生，目前曾在加利福尼亚大学旧金山大学担任临床讲师。这项职业发展建议有两个主要目标。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，其中包括由理查德·洛克斯利（Richard Locksley）博士的指导，理查德·洛克斯利（Richard Locksley）是一个多学科委员会，该委员会旨在提供科学和职业建议，教学课程，促进科学成长和协作的会议，以及实验室管理和专业技能的工作室。其次，莫洛夫斯基博士概述了一项为期5年的研究策略，以检查与脂肪组织过敏性免疫相关的基本问题。肥胖和2型糖尿病的全球患病率显着增加，导致了显着的发病率和死亡率。肥胖会促进脂肪组织的炎症，是胰岛素抵抗和弗兰克糖尿病发展的早期事件。相比之下，许多与过敏性抗螺旋的免疫相关的免疫细胞位于瘦脂肪组织中，并且在肥胖诱导的胰岛素抵抗和糖尿病模型中具有保护性。莫洛夫斯基博士的长期目标是阐明坐标调节，细胞相互作用和代谢健康和疾病中过敏性免疫细胞代谢稳态的个人贡献。该应用的目的是了解促进脂肪组织淋巴细胞功能的信号，包括先天淋巴样2型细胞（ILC2），自适应TH2和调节性T细胞（TREG），以及肥胖症模型中每种细胞类型的代谢稳态的个人贡献。该提议的核心假设是，包括IL-33在内的上皮细胞因子在脂肪组织并协调调节ILC2，TH2和Treg细胞，它们都独特地有助于代谢结果。 Molofsky博士将通过追求三个具体目标来实现该提案的目标。在AIM 1中，Molofsky博士将检验以下假设：包括IL-33和TSLP在内的上皮细胞因子的组合促进脂肪组织ILC2功能和细胞因子分泌。使用独特的ILC2缺乏动物，将评估ILC2的精确代谢影响。在AIM 2中，Molofsky博士将解决脂肪组织中适应性Th2细胞的调节和代谢贡献，以检验以下假设：TH2细胞提供了一种随着年龄和蠕虫感染后与过敏性免疫相关细胞因子的产生的机制。在AIM 3中，Molofsky博士将检验上皮细胞因子IL的假设 33，以及未知的ILC2因子，协同调节并支持脂肪组织Treg，它们在肥胖诱导的胰岛素抵抗模型中具有保护性。该项目与糖尿病研究以及NIH和NIDDK的任务有关，因为它有可能揭示与肥胖症和糖尿病发育相关的新型细胞和分子靶标。