Abdominal Adipose Tissue Inflammation

描述(申请人提供)：该应用程序将检查不同的动脉粥样硬化病理，以了解在高脂血症小鼠的腹主动脉中发现的恶化病变的原因，这些小鼠受到慢性、系统性促炎刺激的挑战。当高胆固醇血症低密度脂蛋白受体基因敲除(LDLR-/-)小鼠多次暴露于有效的Toll样受体(TLR)激动剂时，腹主动脉内的损害严重，而胸主动脉内的损害轻微。我们将检验这一假设，即胸主动脉和腹主动脉周围脂肪组织炎症特征的差异解释了动脉粥样硬化严重程度的区域差异。慢性炎症疾病模型是一只LDLR-/-小鼠，喂食高脂饮食(HFD)，并反复暴露于合成的TLR2/1激动剂Pam3。在目标1中，注射Pam3的小鼠的胸主动脉和腹主动脉组织片段将与暴露于载体对照组的小鼠的可比组织片段进行比较。基因表达和细胞因子(包括脂肪因子)的产生将在组织片段和脂肪组织内的多个细胞中进行检测，包括脂肪细胞、巨噬细胞、树突状细胞、白细胞、内皮细胞和成纤维细胞。分离的腹部血管间质细胞将与胶原酶凝胶包埋的胸部脂肪组织进行共培养。这一数据应该支持这样的假设，即胸主动脉周围脂肪组织内的环境在功能上不同于腹主动脉周围脂肪组织的促炎环境。目的2将验证一种假设，即表达TLR2/1的骨髓来源的细胞在高脂饲料喂养和Pam3暴露的LDLR-/-小鼠中所见的炎症诱导的严重腹壁动脉粥样硬化中是必不可少的。这一想法将通过对LDLR-/-小鼠和来自LDLR-/-TLR2-/-双突变小鼠和LDLR-/-对照小鼠的骨髓捐赠者进行骨髓移植来验证。将检查炎症和主动脉粥样硬化的进展情况。目标3将检验这种脂肪组织炎症可以预防的假设。脂肪组织中单眼脂肪细胞中PPAR3的激活可以促进脂联素的产生，从而减轻炎症和减少疾病。这一目标将利用暴露于TLR激动剂的转基因小鼠，这些转基因小鼠仅在脂肪细胞中结构性地表达正常水平的PPAR3。第三个目标将提供对炎症诱导的严重腹部疾病的机械性洞察。总而言之，这些研究将对一种极端的动脉粥样硬化病理提供关键的见解，这种病理与慢性暴露于组织损伤、感染剂和病原体引起的全身炎症有关。 公共卫生相关性：动脉粥样硬化是一个主要的健康问题。肥胖是动脉粥样硬化的一个主要风险因素，在西方社会正在增加。这项应用将直接研究肥胖和慢性炎症之间的联系，慢性炎症促进动脉粥样硬化进展，导致心脏病和中风。

DESCRIPTION (provided by applicant): This application will examine distinct atherosclerosis pathology to understand the cause of the exacerbated lesions found in the abdominal aorta of hyperlipidemic mice challenged with a chronic, systemic proinflammatory stimulus. When hypercholesterolemic Low Density Lipoprotein receptor knockout (LDLr-/-) mice are exposed multiple times to a potent Toll-Like Receptor (TLR) agonist, lesions within the abdominal aorta are severe; whereas lesions within the thoracic aorta are minimal. We will test the hypothesis that differences in the inflammatory characteristics of adipose tissue surrounding the thoracic versus the abdominal aorta account for the regional differences in atherosclerosis severity. The chronic inflammation disease model is an LDLr-/- mouse fed a high fat diet (HFD) and repeatedly exposed to the synthetic TLR2/1 agonist, Pam3. In Aim 1 thoracic and abdominal aortic tissue segments of Pam3 injected mice will be compared to comparable tissue segments from mice exposed to a vehicle control. Gene expression and cytokine (including adipokine) production will be examined in tissue segments and in multiple cells within adipose tissues including adipocytes, macrophages, dendritic cells, leukocytes, endothelial cells and fibroblasts. Isolated abdominal vascular stromal fraction cells will be co cultured with minced thoracic adipose tissues embedded in a collagenase gel. This data should support the hypothesis that the environment within thoracic periaortic adipose tissue is functionally different from the pro inflammatory setting of the periaortic abdominal adipose tissue. Aim 2 will test the hypothesis that TLR2/1 expressing bone marrow-derived cells are essential for the inflammation induced severe abdominal atherosclerosis seen in HFD fed and Pam3 exposed LDLr-/- mice. This idea will be tested by performing bone marrow transplantation of LDLr-/- mice with bone marrow donors from LDLr-/-TLR2-/- double mutant mice and LDLr-/- control mice. Inflammation and aortic atherosclerosis progression will be examined. Aim 3 will test the hypothesis that this adipose tissue inflammation can be prevented. Peroxisome proliferator-activated nuclear receptor gamma (PPAR3) activation in unilocular adipocytes within adipose tissue should promote the production of adiponectin that will mitigate inflammation and reduce disease. This aim will utilize TLR agonist exposed transgenic mice that constitutively express normal levels of PPAR3 in only adipocytes. The third aim will provide mechanistic insight into inflammation- induced severe abdominal disease. Collectively, these studies will provide key insight into an extreme atherosclerosis pathology linked to systemic inflammation resulting from chronic exposure to tissue injury, infectious agents and pathogens. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a major health problem. Obesity, a major risk factor for atherosclerosis, is increasing in Western societies. This application will directly study a link between obesity and the chronic inflammation that promotes atherosclerosis progression leading to heart disease and stroke.