Peritoneal mesothelial cells: Role in obesity and metabolic dysfunction

腹膜间皮细胞：在肥胖和代谢功能障碍中的作用

基本信息

批准号：
9337440
负责人：
Olga Theresa Gupta
金额：
$ 19.06万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9337440
关键词：
Abdomen Abdominal Cavity Adipocytes Adipose tissue Aging Alleles Animal Model Antibodies Architecture Bariatrics Blood Vessels CXCL12 gene CXCL2 gene CXCL6 gene Cell Line Cells Central obesity Cholesterol Comorbidity Coronary Arteriosclerosis Data Development Doxycycline Dyslipidemias Electron Microscopy Employee Strikes Endotoxins Functional disorder Gene Expression Gene Expression Profiling Goals Greater omentum Heart Diseases Human Hypertension Hypertrophy IL6 gene IL8 gene Immune Individual Infiltration Inflammation Inflammatory Institution Insulin Resistance Intra-abdominal Knowledge Label Link Lipids LoxP-flanked allele Measures Mediator of activation protein Membrane Mesothelial Cell Mesothelium Metabolic Metabolic Diseases Metabolism Modeling Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Omentum Operative Surgical Procedures Organ Pathologic Patients Peritoneal Mesothelial Cell Play Production Property Proteins Proteoglycan Research Risk Factors Rodent Model Role Saturated Fatty Acids Signal Transduction Site Stroke Study Subject Study of serum Surface TLR4 gene Testing Therapeutic Intervention Thinness Toll-Like Receptor Pathway Toll-like receptors Transgenic Mice Visceral cell type chemokine cohort cytokine defined contribution experimental study follow-up inflammatory marker interest light microscopy macrophage mesothelin mouse model novel novel therapeutics programs public health relevance response surfactant targeted treatment tissue repair

项目摘要

DESCRIPTION (provided by applicant): Intra-abdominal obesity is a risk factor for type 2 diabetes, dyslipidemia, and coronary artery disease. The omentum, a highly vascularized membrane that covers most of the abdominal cavity, is the predominant intraabdominal site of adipose storage and is thought to play a pathologic role in obesity-related co-morbidities. Tremendous progress has been made in establishing the role of various immune cells and the adipocytes in the development of adipose tissue inflammation; however, other potential inflammatory cell types have not been explored. Particularly, mesothelial cells that line the omentum and are in close contact with underlying adipocytes. Their primary function is to provide a protective, non-adhesive surface within the abdominal cavity by secreting surfactant-like proteoglycans. In addition, mesothelial cells also secrete cytokines, and chemokines, both of which contribute to their multifunctional properties. Notably, peritoneal mesothelial cells express TLR4; this Toll-like receptor is the major mediator of endotoxin and free-fatty acid induced inflammation. Currently, there is a lack of data critically examining the effects of obesit on the morphologic and functional properties of the mesothelial cells. The overall goals of the experiments described in this proposal are to 1) establish a relationship between mesothelial cell inflammation and insulin resistance in the context of human intra-abdominal obesity, and 2) determine the contribution of mesothelial cells to local adipose tissue inflammation. To achieve these goals, we will use both human and animal models of obesity to characterize adipose mesothelial cells. We will also utilize novel conditional mouse models to define the contribution of mesothelial cells to adipose tissue inflammation and to dysregulate the inflammatory programs within the mesothelial cells. The experiments described in this proposal will test the novel hypothesis that mesothelial cells contribute to omental adipose inflammation in obesity. Identification of the pathologic features of omental fat is essential to understanding mechanisms linking obesity to metabolic disease and critical for the development of novel therapeutic strategies to treat metabolic disease.

描述（由申请人提供）：冠状动脉内腹部肥胖是 2 型糖尿病、血脂异常和动脉疾病的危险因素。大网膜是覆盖大部分腔的高度血管化的膜，是腹腔内脂肪储存和沉积的主要部位。人们认为在肥胖相关并发症中发挥着病理作用，在确定各种免疫细胞和脂肪细胞在肥胖发展中的作用方面已经取得了巨大进展。脂肪组织炎症；然而，其他潜在的炎症细胞类型尚未被探索，特别是网膜内的间皮细胞，其主要功能是在腹腔内提供保护性、非粘附性表面。此外，间皮细胞还分泌细胞因子和趋化因子，这两者都有助于其多功能特性。间皮细胞表达 TLR4；这种 Toll 样受体是内毒素和游离脂肪酸诱导的炎症的主要介质，目前缺乏严格研究肥胖对间皮细胞形态和功能特性影响的数据。本提案中描述的实验目标是 1) 在人类腹内肥胖的背景下建立间皮细胞炎症和胰岛素抵抗之间的关系，以及 2) 确定为了实现这些目标，我们将使用人类和动物肥胖模型来表征脂肪间皮细胞，我们还将利用新的条件小鼠模型来定义间皮细胞对脂肪组织炎症的影响。调节间皮细胞内的炎症程序本提案中描述的实验将验证间皮细胞导致肥胖症中网膜脂肪炎症的新假设。大网膜脂肪的病理特征对于理解肥胖与代谢疾病之间的联系机制至关重要，对于开发治疗代谢疾病的新治疗策略也至关重要。