Dendritic Cells and Obesity

 描述（由申请人提供）：虽然已经确定肥胖与慢性、低度炎症状态相关，这有助于肥胖的代谢失调，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。在过去的几年里，我们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的发病机制的贡献。我们最近的工作（附录1）表明，树突状细胞（DC）在肥胖小鼠的肝脏和脂肪组织中升高，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的小鼠可以防止饮食诱导的肥胖症的发展。目前的建议中所解决的问题来自这项工作，并将把我们的重点放在一些新的方向。因此，目前的建议将测试假设，初步数据支持，过量的脂肪酸从脂肪组织输送到肝脏是一个主要的信号启动肝脏免疫系统对营养过剩的反应，由增加的氧化应激驱动，早期事件是DC的招募。我们建议，DC，一旦招募，发挥协调肝脏炎症反应的核心作用，特别是通过他们的能力，激活T细胞和巨噬细胞，可能在门静脉相关淋巴组织。此外，并再次支持的初步数据，我们提出，活性氧（ROS）产生酶，黄嘌呤氧化还原酶（XOR），在介导FFA对肝脏炎症反应的肥胖症的影响中起着至关重要的作用。这些假设将在两个特定的目标，并将使用一些原代细胞培养和小鼠模型，免疫学，代谢，生物化学和分子分析将被应用。我们工作的总体目标，其中这些项目形成一个重要组成部分，是获得健康和疾病的免疫系统改变的机制和功能的综合理解，因为它们涉及代谢调节。

 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.