THROMBOSPONDIN1 MEDIATES MACROPHAGE INFILTRATION INTO ADIPOSE TISSUE AND PROMOTE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 项目1：血栓蛋白1介导巨噬细胞向脂肪组织的渗透并促进肥胖小鼠的动脉粥样硬化 皮书霞·王 描述： 肥胖正在成为一个全球公共卫生问题，并与动脉粥样硬化风险增加有关。越来越多的证据表明，肥胖诱导的慢性低度炎症是肥胖对动脉粥样硬化不利影响的重要机制。血栓蛋白1(TSP1)是一种具有多结构域的多功能细胞外基质蛋白，在血管系统中表现出多种作用，有望促进动脉粥样硬化的发生和发展。TSP1已被证明在饮食或遗传诱导肥胖的小鼠的脂肪组织中上调。此外，最近的研究表明，TSP1在肥胖者的脂肪细胞中表达增加，并与肥胖和脂肪组织炎症呈正相关。初步数据显示，与高脂(HF)喂养的野生型对照相比，高脂(HF)喂养的TSP1缺陷小鼠的脂肪组织显示出渗透的巨噬细胞数量减少。重要的是，尽管小鼠表现出与野生型对照组相似的肥胖水平，但观察到TSP1/-HF喂养的小鼠脂肪组织中巨噬细胞渗入的减少。基于这些研究，我们假设TSP1的特定结构域介导了饮食诱导肥胖的脂肪组织中巨噬细胞浸润的增加，并促进了apoE-/-小鼠的动脉粥样硬化。为了解决这一假设，我们将在AIM 1中确定TSP1导致巨噬细胞黏附和/或迁移增加的特定结构域，并在AIM 2中确定TSP1缺乏是否会减少饮食诱导肥胖的apoE/-小鼠的动脉粥样硬化。这些研究将提供关于TSP1在肥胖相关动脉粥样硬化中作用的新信息，并可能导致治疗这种疾病的靶点的开发。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project 1: Thrombospondin1 mediates macrophage infiltration into adipose tissue and promotes atherosclerosis in obese mice PI Shuxia Wang Description: Obesity is becoming a global public health problem and is associated with an increased risk of atherosclerosis. Accumulating evidence suggests that obesity-induced chronic low-grade inflammation is an important mechanism for the adverse effects of adiposity on atherosclerosis. Thrombospondin1 (TSP1), a multifunctional extracellular matrix protein with multi-domains, exhibits several effects on the vasculature that would be anticipated to contribute to the development and progression of atherosclerosis. TSP1 has been shown to be up-regulated in adipose tissue of mice with diet or genetically induced obesity. Moreover, recent studies demonstrate that TSP1 expression is increased in adipocytes from obese humans and correlates positively to obesity and adipose tissue inflammation. Preliminary data demonstrate that adipose tissue from high fat (HF)-fed TSP1 deficient mice exhibits reduced numbers of infiltrating macrophages compared to HF-fed wild type controls. Importantly, reductions in macrophage infiltration into adipose tissue of TSP1-/- HF-fed mice were observed even though mice exhibited similar levels of obesity as wild type controls. Based on these studies, we hypothesize that specific domains of TSP1 mediate increased macrophage infiltration into adipose tissue with diet-induced obesity and promote atherosclerosis in apoE-/- mice. To address this hypothesis, we will determine the specific domains of TSP1 responsible for increased macrophage adhesion and/or migration in Aim 1 and determine if TSP1 deficiency decreases atherosclerosis in apoE-/- mice with diet-induced obesity in Aim 2. These studies will provide novel information on the role of TSP1 in obesity associated atherosclerosis and may lead to development of therapeutic targets for treatment of this disease.