THROMBOSPONDIN 1 MEDIATES MACROPHAGE INFILTRATION INTO ADIPOSE TISSUE AND PROMOT

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。 肥胖正在成为一个全球公共卫生问题，并与包括动脉粥样硬化在内的心血管疾病风险增加有关。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是一种多功能的细胞外基质蛋白，已被证明在饮食或遗传诱导肥胖的小鼠脂肪组织中表达上调。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。此外，与对照组相比，服用HF的TSP1-/-小鼠脂肪组织和血浆中的肿瘤坏死因子-α和白介素6水平降低。细胞黏附分子ICAM在HF喂养对照组的主动脉内皮细胞中表达增加，但TSP1-/-小鼠没有，这表明TSP1参与了肥胖相关的内皮功能障碍。此外，培养的巨噬细胞与TSP1孵育增加了迁移，而来自TSP1-/-小鼠的巨噬细胞迁移减少。然而，TSP1负责巨噬细胞渗透的特定结构域以及导致肥胖诱导巨噬细胞渗透的TSP1的细胞来源尚不清楚。重要的是，在没有或存在肥胖的情况下，TSP1缺乏对动脉粥样硬化发展的影响尚未确定。这一建议的中心假设是，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。这一假说将通过确定TSP1的特定结构域来验证，TSP1负责增加目标1中巨噬细胞的黏附和/或迁移。在目标2中，我们将确定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。这些研究将为TSP1在肥胖相关动脉粥样硬化中的作用提供新的信息。了解脂肪组织TSP1在脂肪组织炎症调节中的作用及其在饮食诱导肥胖小鼠动脉粥样硬化发生发展中的作用，将有助于制定治疗该疾病的靶点。

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. Obesity is becoming a global public health problem and is associated with an increased risk of cardiovascular diseases including atherosclerosis. Accumulating evidence suggests that obesity-induced chronic low-grade inflammation is an important mechanism for the adverse effects of adiposity on atherosclerosis. Thrombospondin1, a multifunctional extracellular matrix protein, 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. In addition, TNF-alpha and IL-6 levels in adipose tissue and plasma were reduced in HF-fed TSP1-/- mice compared to controls. Expression of the cell adhesion molecule - ICAM was increased in aortic endothelial cells from HF-fed control, but not TSP1-/- mice, suggesting that TSP1 contributes to obesity-associated endothelial dysfunction. Moreover, incubation of cultured macrophages with TSP1 increased migration, while macrophages from TSP1-/- mice exhibited reduced macrophage migration. However, the specific domains of TSP1 responsible for macrophage infiltration, as well as the cell source of TSP1 contributing to obesity-induced macrophage infiltration are unknown. Importantly, effects of TSP1 deficiency on the development of atherosclerosis in the absence or presence of obesity have not been defined. The central hypothesis of this proposal is that specific domains of TSP1 mediate increased macrophage infiltration into adipose tissue with diet-induced obesity and promote atherosclerosis in apoE-/- mice. This hypothesis will be tested by determination of the specific domains of TSP1 responsible for increased macrophage adhesion and/or migration in aim 1. In aim 2, we will determine if TSP1 deficiency decreases atherosclerosis in apoE-/- mice with diet-induced obesity. These studies will provide novel information on the role of TSP1 in obesity associated atherosclerosis. Understanding the role of adipose tissue TSP1 in regulation of adipose tissue inflammation and its role in the development and progression of atherosclerosis in mice with diet-induced obesity will lead to development of therapeutic targets for treatment of this disease.