THROMBOSPONDIN 1 MEDIATES MACROPHAGE INFILTRATION INTO ADIPOSE TISSUE AND PROMOT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肥胖正在成为一个全球性的公共卫生问题，并与包括动脉粥样硬化在内的心血管疾病的风险增加有关。 越来越多的证据表明，肥胖引起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。 凝血酶敏感蛋白1是一种多功能的细胞外基质蛋白，在饮食或遗传性肥胖小鼠的脂肪组织中表达上调。 此外，最近的研究表明，TSP 1的表达增加，在脂肪细胞从肥胖的人和正相关的肥胖和脂肪组织炎症。 初步数据表明，脂肪组织从高脂肪（HF）喂养的TSP 1缺陷型小鼠表现出减少数量的浸润巨噬细胞相比，HF喂养的野生型控制。 重要的是，即使小鼠表现出与野生型对照相似的肥胖水平，也观察到TSP 1-/-HF喂养的小鼠的巨噬细胞浸润到脂肪组织中的减少。 此外，与对照组相比，HF喂养的TSP 1-/-小鼠脂肪组织和血浆中的TNF-α和IL-6水平降低。 细胞粘附分子- ICAM的表达在HF喂养对照的主动脉内皮细胞中增加，但不是TSP 1-/-小鼠，表明TSP 1有助于肥胖相关的内皮功能障碍。 此外，培养的巨噬细胞与TSP 1孵育增加了迁移，而来自TSP 1-/-小鼠的巨噬细胞表现出减少的巨噬细胞迁移。 然而，负责巨噬细胞浸润的TSP 1的特定结构域，以及导致肥胖诱导的巨噬细胞浸润的TSP 1的细胞来源是未知的。 重要的是，在存在或不存在肥胖的情况下，TSP 1缺乏对动脉粥样硬化发展的影响尚未确定。 该建议的中心假设是，TSP 1的特定结构域介导饮食诱导的肥胖症增加的巨噬细胞浸润到脂肪组织中，并促进apoE-/-小鼠的动脉粥样硬化。 将通过确定目标1中负责增加巨噬细胞粘附和/或迁移的TSP 1的特定结构域来检验该假设。 在目标2中，我们将确定TSP 1缺乏是否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TSP 1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TSP 1在调节脂肪组织炎症中的作用及其在饮食诱导的肥胖小鼠动脉粥样硬化的发展和进展中的作用将导致开发用于治疗这种疾病的治疗靶点。

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.