Inflammatory Responses of The Visceral Adipose Tissue Microcirculation

内脏脂肪组织微循环的炎症反应

• 批准号: 9906206
• 负责人: SATORU EGUCHI
• 金额: $ 47.71万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906206
• 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; Exposure to; 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; 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; Visceral fat; Weight Gain; Western Blotting; Work; absorption; calpain inhibitor; calpastatin; 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

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.

项目总结/摘要 超重和肥胖个体的脂肪库不断扩大，会发生病理性白细胞浸润， 发生在器官组织微循环中的过程。因此，内脏脂肪库成为 发炎，功能失调，导致胰岛素抵抗，心血管疾病，癌症和关节炎， 其发病率在美国不断增长的肥胖人群中不断增加。准确的时间进程和 热量摄入过多引起白细胞浸润的脂肪库扩大的机制 仍然不明确，这限制了对肥胖人群的治疗干预。出版的作品，沿着新的 这里提供的初步数据揭示了脂肪组织内皮细胞的新作用， 微循环在这些过程中。我们的初步数据表明钙的机械作用- 餐后循环白细胞向内脏脂肪浸润中依赖性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-内皮细胞相互作用的上调 仓库。结果，脂肪组织受到浸润的炎症作用， 白细胞本计画的长期目标为：1）了解分子与细胞决定因子 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)研究负责餐后激活内皮钙蛋白酶的信号通路; 3） 研究这些过程对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，沿着以下内容 生理学和生物化学技术：活体显微镜检查，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 这项工作的结果将促进我们对启动和维持这些系统的综合机制的理解， 超重/肥胖生物体中的脂肪组织炎症和相关病症。