Inflammatory Responses of The Visceral Adipose Tissue Microcirculation

内脏脂肪组织微循环的炎症反应

基本信息

批准号：
9318746
负责人：
SATORU EGUCHI
金额：
$ 49.94万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9318746
关键词：
Acute Adipocytes Adipose tissue Affect Arthritis Biochemical Biochemistry Blood capillaries Calcium Calories Calpain Cardiovascular Diseases Cardiovascular system Caspase Cell Adhesion Molecules Cells Chronic Clinical Data Consumption Data Diabetes Mellitus Diet Disease Endothelial Cells Endothelium Epidermal Growth Factor Receptor Event Experimental Animal Model Extracellular Signal Regulated Kinases Fatty acid glycerol esters Flow Cytometry Functional disorder Gatekeeping Genetic Goals Health Histology Homeostasis Human Hyperlipidemia Immune system Immunofluorescence Immunologic Immunohistochemistry In Vitro Incidence Individual Infiltration Inflammation Inflammatory Inflammatory Response Insulin Resistance Intake Knockout Mice Laboratories Lead Leukocyte Trafficking Leukocytes Link Lipids MEKs Macronutrients Nutrition Malignant Neoplasms Metabolic Microcirculation Modeling Molecular Molecular Target Mus Nonesterified Fatty Acids Obesity Organ Organism Overweight P-Selectin Pathologic Peptide Hydrolases Pharmacology Phenotype Phosphorylation Physiological Physiology Play Population Procedures Process Protein Isoforms Publishing RNA Regulation Research Research Personnel Rodent Role Secondary to Selectins Signal Pathway Signal Transduction System Techniques Technology Testing Therapeutic Intervention Thinness Time Tissues Transactivation Transgenic Mice Triglycerides Up-Regulation Vascular Endothelium Vascular System Virulence Factors Visceral Weight Gain Western Blotting Work absorption calpain inhibitor calpastatin capillary cellular targeting endothelial dysfunction experience experimental study in vivo intravital microscopy leukocyte activation lipoprotein lipase mortality mouse model novel novel therapeutic intervention overexpression postcapillary venule prevent response subcutaneous theories

项目摘要

PROJECT SUMMARY / ABSTRACT The expanding fat depots of overweight and obese individuals experience pathologic leukocyte infiltration, a process that takes place in the microcirculation of organ tissue. Thus, the visceral adipose depots become inflamed, dysfunctional and contributes to insulin resistance, cardiovascular disease, cancer and arthritis, whose incidence is gaining in the ever-growing obese population of the USA. The precise time-course and mechanisms by which excessive calorie intake instigates leukocyte infiltration in expanding adipose depots remain undefined, which limits therapeutic interventions in obese humans. Published work, along with new preliminary data presented here, uncover a novel role for the endothelium of the adipose tissue microcirculation in these processes. Our preliminary data demonstrate a mechanistic role for the calcium- dependent cysteine protease calpain in post-prandial infiltration of circulating leukocytes into visceral fat depots. Our working hypothesis is that lipids overload causes post-prandial activation of endothelial-expressed calpain via transactivation of the EGF receptor, with subsequent upregulation of leukocyte-endothelium interactions in the microcirculation of the visceral fat depots. As a result, adipose tissue is subjected to the inflammatory action of infiltrating leukocytes. The long-term goals of this project are: 1) to understand the molecular and cellular determinants that makes the microcirculation of visceral fat highly responsive to post-prandial absorption of macronutrients; 2) to investigate the signaling pathways responsible for post-prandial activation of endothelial calpain; 3) to study the impact of these processes on the postprandial and chronic inflammatory responses of the adipose tissue. Toward these goals, we will utilize knockout and transgenic mouse technology along with the following physiology and biochemistry techniques: intravital microscopy, cells and tissue isolation procedures, western blot analysis, immunohistochemistry and immunofluorescence, interfering RNA technology. We hope that the results of this work will advance our understanding of the integrated mechanisms that initiate and maintain adipose tissue inflammation and related disorders in the overweight/obese organism.

项目概要/摘要超重和肥胖个体不断扩大的脂肪库会经历病理性白细胞浸润，这是一种器官组织微循环中发生的过程。因此，内脏脂肪库变成发炎、功能失调并导致胰岛素抵抗、心血管疾病、癌症和关节炎，在美国不断增长的肥胖人口中，其发病率正在上升。准确的时间进程和过量热量摄入促使白细胞浸润扩大脂肪库的机制仍未定义，这限制了肥胖人群的治疗干预。已发表的作品以及新作品这里提供的初步数据揭示了脂肪组织内皮的新作用这些过程中的微循环。我们的初步数据证明了钙的机械作用餐后循环白细胞浸润内脏脂肪中依赖的半胱氨酸蛋白酶钙蛋白酶仓库。我们的工作假设是，脂质超载会导致餐后激活通过 EGF 受体的反式激活，内皮表达的钙蛋白酶，随后内脏脂肪微循环中白细胞-内皮相互作用的上调仓库。结果，脂肪组织受到浸润的炎症作用。白细胞。该项目的长期目标是：1）了解分子和细胞决定因素这使得内脏脂肪的微循环对餐后大量营养素的吸收高度敏感； 2) 研究餐后内皮钙蛋白酶激活的信号通路； 3）到研究这些过程对脂肪餐后和慢性炎症反应的影响组织。为了实现这些目标，我们将利用基因敲除和转基因小鼠技术以及以下技术生理学和生物化学技术：活体显微镜、细胞和组织分离程序、西方印迹分析、免疫组织化学和免疫荧光、干扰RNA技术。我们希望这项工作的结果将增进我们对启动和维持的综合机制的理解超重/肥胖机体的脂肪组织炎症和相关疾病。