Abdominal Adipose Tissue Inflammation

腹部脂肪组织炎症

• 批准号: 8403782
• 负责人: PETER S TOBIAS
• 金额: $ 22.55万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403782
• 关键词: Abdomen; Accounting; Adipocytes; Adipose tissue; Agonist; Aorta; Atherosclerosis; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Brown Fat; Cell Fraction; Cells; Characteristics; Chest; Chronic; Coculture Techniques; Collagen; Collagen Type I; Data; Dendritic Cells; Descending aorta; Diet; Disease; Disease model; Dose-Rate; Endothelial Cells; Environment; Exposure to; Fatty acid glycerol esters; Fibroblasts; Functional disorder; Gel; Gene Expression; Health; Heart Diseases; Human; Human body; Hypertrophy; Immune; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Injury; Knock-out; Knockout Mice; Leptin; Lesion; Leukocytes; Link; Low Density Lipoprotein Receptor; Lymphocyte; Measures; Modeling; Mus; Mutant Strains Mice; Nuclear Receptors; Obesity; Pathology; Periodontal Diseases; Peroxisome Proliferators; Phenotype; Play; Population; Porphyromonas gingivalis; Process; Production; Receptor Activation; Risk; Risk Factors; Role; Severities; Site; Societies; Specificity; Stimulus; Stroke; TLR2 gene; Testing; Thoracic aorta; Time; Tissue Embedding; Tissues; Toll-like receptors; Transgenic Mice; Vascular Diseases; abdominal aorta; adipokines; adiponectin; cell type; chemokine; collagenase; cytokine; experience; feeding; in vivo Model; insight; macrophage; microorganism; novel; pathogen; prevent; receptor; regional difference; resistin; sensor

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.

该应用将检查独特的动脉粥样硬化病理学，以了解恶化的原因 在高脂症小鼠的腹主动脉中发现的病变，面临着慢性全身性的挑战 促炎刺激。当高胆固醇低密度脂蛋白受体敲除（LDLR - / - ）时 小鼠多次暴露于潜在的Toll样受体（TLR）激动剂，腹部病变 主动脉很严重；而胸主动脉内的病变很小。我们将检验以下假设 胸部周围脂肪组织的炎症特征与腹部的差异 主动脉解释了动脉粥样硬化严重程度的区域差异。慢性感染疾病模型 是喂养高脂肪饮食（HFD）的LDLR - / - 小鼠，并反复暴露于合成TLR2/1激动剂PAM3。 在AIM 1中，将在PAM3注射小鼠的胸腔和腹主动脉组织段与 暴露于车辆控制的小鼠的可比组织段。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时机内的多个细胞中进行检查 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。隔离的腹部 血管基质分数细胞将与嵌入在A 胶原酶凝胶。该数据应支持以下假设 脂肪组织在功能上与腹部腹部脂肪的炎性炎症环境不同 组织。 AIM 2将检验以下假设：TLR2/1表达骨髓衍生的细胞对于 炎症诱导的HFD FED和PAM3暴露于LDLR - / - 小鼠中的严重动脉粥样硬化。 该想法将通过用骨髓供体对LDLR - / - 小鼠进行骨髓移植来测试 来自LDLR - / - TLR2 - / - 双重突变小鼠和LDLR - / - 对照小鼠。炎症和主动脉粥样硬化 将检查进展。 AIM 3将检验以下假设，即这种脂肪组织注射可以是 阻止。单眼激活过氧化物组增殖物激活的核接收器伽马（PPAR？）激活 脂肪组织中的脂肪细胞应促进脂联素的产生，以减轻注射 并减少疾病。这个目标将利用构成表达的TLR激动剂暴露的转基因小鼠 仅在脂肪细胞中的正常pPAR。第三个目标将为炎症提供机械洞察力 - 诱发严重的腹部疾病。总的来说，这些研究将为极端提供关键的见解 动脉粥样硬化病理学与由于长期暴露于组织损伤而导致的全身感染有关的病理学， 传染性药物和病原体。