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.

该应用程序将检查一个不同的动脉粥样硬化病理，以了解恶化的原因。 在用慢性全身性 促炎刺激当高胆固醇血症低密度脂蛋白受体敲除（LDLr-/-） 将小鼠多次暴露于有效的Toll样受体（TLR）激动剂， 主动脉是严重的;而胸主动脉内的病变是最小的。我们将检验这个假设， 胸部与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差异。慢性炎症疾病模型 是喂食高脂饮食（HFD）并反复暴露于合成的TLR 2/1激动剂Pam 3的LDL r-/-小鼠。 在目标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注射Pam 3的小鼠的胸主动脉和腹主动脉组织区段进行比较。 来自暴露于溶剂对照的小鼠的相当的组织片段。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测脂肪因子）的产生， 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。孤立性腹部 血管基质部分细胞将与切碎的胸脂肪组织共培养，包埋在 胶原酶凝胶。该数据应支持胸主动脉周围环境 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.目的2将检验表达TLR 2/1的骨髓源性细胞对于肿瘤的发生是必需的这一假设。 在HFD喂养和Pam 3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。 这一想法将通过用骨髓供体进行LDLr-/-小鼠的骨髓移植来检验 来自LDLr-/-TLR 2-/-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。目的3将检验这种脂肪组织炎症可以被 防止。过氧化物酶体增殖物激活核受体γ（PPAR <$）激活在单房性 脂肪组织内的脂肪细胞应该促进脂联素的产生， 减少疾病。该目的将利用TLR激动剂暴露的转基因小鼠，其组成性表达 正常水平的过氧化物酶体增殖物激活物受体。第三个目标将提供对炎症的机械见解- 引发严重的腹部疾病。总的来说，这些研究将提供对极端情况的关键见解 动脉粥样硬化病理学与由慢性暴露于组织损伤引起的全身性炎症有关， 传染源和病原体。