Abdominal Adipose Tissue Inflammation

这个应用程序将检查一种独特的动脉粥样硬化病理，以了解恶化的原因 慢性全身性高脂血症小鼠腹主动脉病变 促炎症刺激。高胆固醇血症低密度脂蛋白受体基因敲除(LDLR-/-) 小鼠多次暴露于一种强大的Toll样受体(TLR)激动剂，即腹部损伤 大动脉病变严重，而胸主动脉内病变轻微。我们将检验这一假设 胸腹部周围脂肪组织炎症特征的差异 动脉粥样硬化严重程度的区域性差异是由主动脉引起的。慢性炎症性疾病模型 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Aim 1中，将Pam3注射小鼠的胸主动脉和腹主动脉组织片段与 暴露在车辆对照组中的小鼠的类似组织片段。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。离体腹 血管基质细胞将与切片的胸腔脂肪组织进行共培养。 胶原酶凝胶。这一数据应该支持这样的假设：胸主动脉周围环境 脂肪组织在功能上不同于腹主动脉周围脂肪的促炎环境 组织。目的2将验证这样的假设，即表达TLR2/1的骨髓来源的细胞对 炎症导致严重的腹部动脉粥样硬化，在饲喂HFD和Pam3暴露的LDLR-/-小鼠中可见。 这一想法将通过对有骨髓捐赠者的LDLR-/-小鼠进行骨髓移植来检验 来自LDLR-/-TLR2-/-双突变小鼠和LDLR-/-对照小鼠。炎症与主动脉粥样硬化 将检查进展情况。目标3将检验这一假设，即这种脂肪组织炎症可能是 被阻止了。单眼过氧化酶体增殖物激活核受体γ(PPAR)的激活 脂肪组织中的脂肪细胞应该促进脂联素的产生，从而减轻炎症 并减少疾病。这一目标将利用暴露于TLR激动剂的转基因小鼠，这些转基因小鼠结构性地表达 仅在脂肪细胞中PPAR的正常水平。第三个目标将提供对炎症的机械性洞察- 导致严重的腹部疾病。总的来说，这些研究将提供对极端情况的关键洞察 动脉粥样硬化病理与慢性暴露于组织损伤引起的全身炎症有关， 感染剂和病原体。

This application will examine a 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 (PPAR¿) 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 PPAR¿ 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.