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，以了解慢性全身性促炎刺激下高脂血症小鼠腹主动脉病变加重的原因。当高胆固醇血症低密度脂蛋白受体敲除（LDLr-/-）小鼠多次暴露于强效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很小。我们将检验胸主动脉和腹主动脉周围脂肪组织炎症特征的差异导致动脉粥样硬化严重程度的区域差异的假设。慢性炎症疾病模型是一只LDLr-/-小鼠，喂食高脂肪饮食（HFD）并反复暴露于合成的TLR2/1激动剂Pam3。在Aim 1中，将Pam3注射小鼠的胸腹主动脉组织段与暴露于载体对照的小鼠的可比组织段进行比较。基因表达和细胞因子（包括脂肪因子）的产生将在组织段和脂肪组织内的多种细胞中进行检查，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。分离的腹腔血管间质部分细胞将与包埋在胶原酶凝胶中的切碎的胸腔脂肪组织共同培养。这些数据应该支持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的假设。目的2将验证在HFD喂养和Pam3暴露的LDLr-/-小鼠中，表达TLR2/1的骨髓源性细胞对炎症诱导的严重腹腔动脉粥样硬化至关重要的假设。这一想法将通过对LDLr-/-小鼠进行骨髓移植来验证，骨髓供体来自LDLr-/- tlr2 -/-双突变小鼠和LDLr-/-对照小鼠。检查炎症和动脉粥样硬化的进展。目的3将检验这种脂肪组织炎症可以预防的假设。在脂肪组织内的单眼脂肪细胞中，过氧化物酶体增殖体激活核受体γ (PPAR3)的激活应促进脂联素的产生，从而减轻炎症和减少疾病。该目的将利用TLR激动剂暴露的转基因小鼠，这些小鼠仅在脂肪细胞中组成性地表达正常水平的PPAR3。第三个目标将提供机制洞察炎症引起的严重腹部疾病。总的来说，这些研究将为研究与慢性暴露于组织损伤、感染因子和病原体引起的全身性炎症有关的极端动脉粥样硬化病理提供关键见解。

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.