Abdominal Adipose Tissue Inflammation

腹部脂肪组织炎症

基本信息

批准号：
8242283
负责人：
Linda K Curtiss
金额：
$ 28.43万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242283
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

项目摘要

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.

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学，以了解在受到慢性、全身性促炎刺激的高脂血症小鼠的腹主动脉中发现的恶化病变的原因。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，腹主动脉内的病变会很严重；而胸主动脉内的病变很小。我们将检验这样一个假设：胸主动脉和腹主动脉周围脂肪组织炎症特征的差异导致了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) 并反复暴露于合成 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暴露于载体对照的小鼠的类似组织片段进行比较。将在组织片段和脂肪组织内的多个细胞（包括脂肪细胞、巨噬细胞、树突细胞、白细胞、内皮细胞和成纤维细胞）中检查基因表达和细胞因子（包括脂肪因子）的产生。分离的腹部血管基质部分细胞将与包埋在胶原酶凝胶中的切碎的胸部脂肪组织共培养。该数据应该支持以下假设：胸部主动脉周围脂肪组织内的环境在功能上不同于腹部主动脉周围脂肪组织的促炎环境。目标 2 将检验以下假设：表达 TLR2/1 的骨髓来源细胞对于 HFD 喂养和 Pam3 暴露的 LDLr-/- 小鼠中观察到的炎症诱导的严重腹部动脉粥样硬化至关重要。这一想法将通过对来自 LDLr-/-TLR2-/- 双突变小鼠和 LDLr-/- 对照小鼠的骨髓供体进行 LDLr-/- 小鼠骨髓移植来验证。将检查炎症和主动脉粥样硬化进展。目标 3 将检验这种脂肪组织炎症可以预防的假设。脂肪组织内的单房脂肪细胞中过氧化物酶体增殖物激活核受体 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。该目标将利用暴露于 TLR 激动剂的转基因小鼠，该小鼠仅在脂肪细胞中组成性表达正常水平的 PPAR3。第三个目标将提供对炎症引起的严重腹部疾病的机制见解。总的来说，这些研究将为了解与慢性暴露于组织损伤、感染因子和病原体引起的全身炎症有关的极端动脉粥样硬化病理学提供重要见解。公共卫生相关性：动脉粥样硬化是一个主要的健康问题。肥胖是动脉粥样硬化的主要危险因素，在西方社会中日益增多。该应用程序将直接研究肥胖与慢性炎症之间的联系，慢性炎症会促进动脉粥样硬化进展，从而导致心脏病和中风。