Dendritic Cells and Obesity

树突状细胞和肥胖

• 批准号: 9107446
• 负责人: ROBERT M O'DOHERTY
• 金额: $ 36.72万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107446
• 关键词: Address; Adipose tissue; Area; Automobile Driving; Biochemical; Cells; Chronic; Data; Dendritic Cells; Development; Diabesity; Diet; Dietary Fatty Acid; Disease; Dyslipidemias; Enzymes; Epidemic; Event; Fatty Acids; Goals; Health; Immune; Immune response; Immune system; Immunophenotyping; Infiltration; Inflammation; Inflammatory Response; Insulin Resistance; Left; Liver; Location; Lymphoid Tissue; Mediating; Metabolic; Molecular Analysis; Mononuclear; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Overnutrition; Oxidative Stress; Pathogenesis; Physical activity; Play; Prevalence; Primary Cell Cultures; Publishing; Reactive Oxygen Species; Recruitment Activity; Regulation; Role; Saturated Fatty Acids; Signal Transduction; Societies; Surface; T-Lymphocyte; Testing; Tissues; Visceral; Volatile Fatty Acids; Work; XDH gene; gut microbiota; in vivo Model; macrophage; mouse model; novel; programs; response

 DESCRIPTION (provided by applicant): Although it is well established that obesity is associated with a state of chronic, low-grade inflammation, which contributes to the metabolic dysregulation of obesity, in many ways we have only begun to scratch the surface of this important area of study. Our work over the last number of years has focused on understanding the contribution of a number of resident liver immune cells to the pathogenesis of the obese liver immunophenotype and associated metabolic abnormalities. Our most recent work (Appendix 1) demonstrated that dendritic cells (DC) are elevated in liver and adipose tissue of obese mice, that depleting or increasing DC alters tissue macrophage and T-cell content, and that mice lacking DC are protected against the development of diet-induced obesity. Questions addressed in the current proposal arise from this work, and will take our focus in a number of novel directions. Thus, the current proposal will test hypotheses, supported by preliminary data, that excessive fatty acid delivery to the liver from adipose tissue is a primary signal initiating the lver immune system response to overnutrition, driven by increased oxidative stress, and that an early event is the recruitment of DC. We propose that DC, once recruited, play a central role in coordinating the liver inflammatory response, specifically by their capacity to activate T-cells an macrophages, possibly at portal associated lymphoid tissue. Furthermore, and again supported by preliminary data, we propose that the reactive oxygen species (ROS) producing enzyme, xanthine oxidoreductase (XOR), plays a critical role in mediating the effects of FFA on liver inflammatory responses in obesity. These hypotheses will be addressed in two specific aims, and will use a number of primary cell culture and mouse models, to which immunological, metabolic, biochemical and molecular analysis will be applied. The overarching goal of our work, of which these projects form an important component, is to obtain an integrated understanding of the mechanisms and functions of immune system alterations in health and disease as they pertain to metabolic regulation.

 描述（由申请人提供）：虽然众所周知，肥胖与慢性、低度炎症状态有关，而慢性、低度炎症会导致肥胖的代谢失调，但在许多方面，我们才刚刚开始触及这一重要研究领域的表面。我们过去几年的工作重点是了解一些常驻肝脏免疫细胞对肥胖肝脏免疫表型和相关代谢异常发病机制的贡献。我们最近的工作（附录 1）表明，肥胖小鼠的肝脏和脂肪组织中的树突状细胞 (DC) 升高，减少或增加 DC 会改变组织巨噬细胞和 T 细胞含量，并且缺乏 DC 的小鼠可以免受饮食引起的肥胖的影响。当前提案中解决的问题源于这项工作，并将把我们的注意力集中在许多新颖的方向上。因此，目前的提议将测试由初步数据支持的假设，即从脂肪组织向肝脏输送过量脂肪酸是启动肝脏免疫系统对营养过剩做出反应的主要信号，由氧化应激增加驱动，并且早期事件是 DC 的招募。我们认为，DC 一旦被招募，就会在协调肝脏炎症反应中发挥核心作用，特别是通过它们激活 T 细胞和巨噬细胞的能力，可能在门脉相关的淋巴组织中。此外，在初步数据的支持下，我们提出活性氧（ROS）产生酶黄嘌呤氧化还原酶（XOR）在介导FFA对肥胖肝脏炎症反应的影响中发挥着关键作用。这些假设将在两个具体目标中得到解决，并将使用许多原代细胞培养物和小鼠模型，并应用免疫学、代谢、生化和分子分析。我们工作的总体目标（这些项目是其中的重要组成部分）是获得对健康和疾病中免疫系统改变与代谢调节有关的机制和功能的综合理解。