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.

该应用程序将检查独特的动脉粥样硬化病理学，以了解恶化的原因 在患有慢性、全身性慢性疾病的高脂血症小鼠的腹主动脉中发现病变 促炎刺激。当高胆固醇血症低密度脂蛋白受体敲除（LDLr-/-）时 小鼠多次暴露于强效 Toll 样受体 (TLR) 激动剂，腹部病变 主动脉严重；而胸主动脉内的病变很小。我们将检验以下假设： 胸部和腹部周围脂肪组织炎症特征的差异 主动脉导致动脉粥样硬化严重程度的区域差异。慢性炎症疾病模型 是一只喂食高脂肪饮食 (HFD) 并反复接触合成 TLR2/1 激动剂 Pam3 的 LDLr-/- 小鼠。 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 来自暴露于载体对照的小鼠的可比较的组织片段。基因表达和细胞因子（包括 将在组织片段和脂肪组织内的多个细胞中检查脂肪因子）的产生，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。孤立腹部 血管基质部分细胞将与嵌入的切碎的胸部脂肪组织共培养 胶原酶凝胶。该数据应该支持以下假设：胸主动脉周围环境 脂肪组织在功能上不同于主动脉周围腹部脂肪的促炎环境 组织。目标 2 将检验以下假设：表达 TLR2/1 的骨髓来源细胞对于 在 HFD 喂养和 Pam3 暴露的 LDLr-/- 小鼠中观察到炎症诱导严重的腹部动脉粥样硬化。 这个想法将通过对骨髓捐赠者进行 LDLr-/- 小鼠的骨髓移植来验证 来自LDLr-/-TLR2-/-双突变小鼠和LDLr-/-对照小鼠。炎症和主动脉粥样硬化 将检查进展情况。目标 3 将检验这一假设：这种脂肪组织炎症可能是由 阻止了。单眼过氧化物酶体增殖物激活核受体γ (PPAR¿) 激活 脂肪组织内的脂肪细胞应促进脂联素的产生，从而减轻炎症 并减少疾病。该目标将利用暴露于 TLR 激动剂的转基因小鼠，该小鼠组成型表达 仅在脂肪细胞中 PPAR 处于正常水平。第三个目标将提供对炎症的机制洞察—— 诱发严重的腹部疾病。总的来说，这些研究将为极端情况提供重要的见解。 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， 传染源和病原体。