Abdominal Adipose Tissue Inflammation

描述（由申请人提供）：本申请将检查不同的动脉粥样硬化病理学，以了解慢性全身性促炎刺激激发的高脂血症小鼠腹主动脉中发现的病变加重的原因。当高胆固醇血症低密度脂蛋白受体敲除（LDLr-/-）小鼠多次暴露于有效的Toll样受体（TLR）激动剂时，腹主动脉内的病变是严重的;而胸主动脉内的病变是最小的。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可以解释动脉粥样硬化严重程度的区域差异。慢性炎症疾病模型是喂食高脂肪饮食（HFD）并反复暴露于合成TLR 2/1激动剂Pam 3的LDLr-/-小鼠。在目的1中，将注射Pam 3的小鼠的胸主动脉和腹主动脉组织区段与来自暴露于媒介物对照的小鼠的相当的组织区段进行比较。将在组织片段和脂肪组织内的多个细胞（包括脂肪细胞、巨噬细胞、树突细胞、白细胞、内皮细胞和成纤维细胞）中检查基因表达和细胞因子（包括脂肪因子）产生。将分离的腹部血管基质部分细胞与包埋在胶原酶凝胶中的切碎的胸部脂肪组织共培养。该数据应支持以下假设：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将检验表达TLR 2/1的骨髓衍生细胞对于在HFD喂养和Pam 3暴露的LDLr-/-小鼠中观察到的炎症诱导的严重腹部动脉粥样硬化是必需的这一假设。将通过用来自LDLr-/-TLR 2-/-双突变小鼠和LDLr-/-对照小鼠的骨髓供体进行LDLr-/-小鼠的骨髓移植来测试该想法。将检查炎症和主动脉粥样硬化进展。目的3将检验这种脂肪组织炎症可以预防的假设。脂肪组织内的单房脂肪细胞中的过氧化物酶体增殖物激活的核受体γ（PPAR 3）激活应促进脂联素的产生，脂联素将减轻炎症并减少疾病。该目的将利用TLR激动剂暴露的转基因小鼠，其仅在脂肪细胞中组成型表达正常水平的PPAR 3。第三个目标将提供炎症引起的严重腹部疾病的机制见解。总的来说，这些研究将提供关键的洞察极端动脉粥样硬化病理与全身性炎症引起的慢性暴露于组织损伤，传染性病原体和病原体。 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主要危险因素，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.