Adipose autotaxin: a novel link between obesity and cardiovascular disease

脂肪自分泌运动因子：肥胖与心血管疾病之间的新联系

• 批准号: 8994168
• 负责人: Susan S. Smyth
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994168
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attention; Biological Models; Blood; Blood Vessels; Body mass index; Cardiovascular Diseases; Cardiovascular system; Caring; Cause of Death; Cessation of life; Chronic; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Enzymes; Exhibits; Experimental Models; Fatty acid glycerol esters; G-Protein-Coupled Receptors; Gap Junctions; Genetic; Genetic Polymorphism; Goals; Grant; Health; Healthcare; Healthcare Systems; Human; Hypertension; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Insulin Resistance; Link; Lipids; Liquid substance; Lysophospholipase; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Medical; Medical center; Mus; Myocardial Infarction; Obese Mice; Obesity; Obesity associated cardiovascular disease; Overweight; Permeability; Phosphoric Monoester Hydrolases; Plasma; Play; Positioning Attribute; Prevention; Production; Reagent; Recombinants; Reporting; Research; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Source; Stroke; System; Testing; United States; Vascular Diseases; Veterans; Work; atherothrombosis; base; cardiovascular disorder risk; cost; disability; disorder risk; extracellular; feeding; inhibitor/antagonist; innovation; inorganic phosphate; lipid metabolism; lysophosphatidic acid; macrophage; migration; monocyte; mouse model; novel; novel strategies; prevent; programs; response to injury; small molecule; vascular inflammation

DESCRIPTION (provided by applicant): Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. The medical costs associated with obesity strain the VA health care system. Obesity is an established risk factor for cardiovascular disease (CVD) and stroke, and the cardiovascular complications of obesity are a leading cause of potentially preventable death in Veterans. In addition to contributing to traditional CVD risk factors, obesity is also characterized by a chronic sub-acute inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Inflamed adipose tissue may uniquely contribute to systemic inflammatory mediators that promote the development of atherosclerosis. A better understanding of the role of adipose tissue in generating inflammatory mediators will ultimately result in identification of novel strategies to prevent and treat associated CVD. Recent evidence and our own findings indicate that adipose tissue contributes to systemic levels of the secreted lysophospholipase D autotaxin (ATX). ATX is responsible for production of extracellular, biologically active lysophosphatidic acid (LPA), a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids that is positioned to play a role in human health and disease. Based on observations that ATX expression increases with adiposity and demonstrated effects of ATX and LPA on monocyte migration and endothelial permeability, we propose the central hypothesis that signaling pathways regulated by ATX contribute to obesity associated inflammation and the development of atherosclerosis. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in two specific aims. In Aim One, we will identify the role of adipose derived ATX in local and systemic inflammation. In Aim Two, we will identify the role of adipose-derived ATX in the development of atherosclerosis. The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling, namely role of adipose-derived ATX in biologic signaling mediated by LPA and its role in atherosclerosis These results will be significant, because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of the cardiovascular complications of obesity in humans.

描述（由申请人提供）： 肥胖和肥胖相关的心血管并发症是美国日益增加的健康负担。2000年，一项对在退伍军人医疗中心接受治疗的近200万退伍军人的分析表明，约68%的人超重，约37%的人肥胖。与肥胖相关的医疗费用使退伍军人管理局的医疗保健系统不堪重负。肥胖是心血管疾病（CVD）和中风的既定危险因素，肥胖的心血管并发症是退伍军人潜在可预防死亡的主要原因。除了促成传统的CVD风险因素之外，肥胖的特征还在于慢性亚急性炎症状态，其中脂肪中有巨噬细胞浸润并且脂肪组织产生炎症介质。发炎的脂肪组织可能是唯一的全身炎症介质，促进动脉粥样硬化的发展。更好地了解脂肪组织在产生炎症介质中的作用将最终导致识别预防和治疗相关CVD的新策略。最近的证据和我们自己的研究结果表明，脂肪组织有助于分泌溶血磷脂酶D自分泌运动因子（ATX）的全身水平。ATX负责细胞外生物活性溶血磷脂酸（LPA）的产生，LPA是一种以生理相关水平存在于血浆和其他生物液体中的生物活性脂质，在人类健康和疾病中发挥作用。基于ATX表达随肥胖而增加的观察结果以及ATX和LPA对单核细胞迁移和内皮渗透性的作用，我们提出了由ATX调节的信号传导途径有助于肥胖相关炎症和动脉粥样硬化发展的中心假设。我们将使用最先进的遗传学和药理学方法在两个特定目标中测试我们的中心假设。在目的一中，我们将确定脂肪来源的ATX在局部和全身炎症中的作用。在目标二中，我们将确定脂肪源性ATX在动脉粥样硬化发展中的作用。这项资助的目的是提供一种手段来解决溶血脂质信号传导领域中一个主要的未解决的问题，即脂肪来源的ATX在LPA介导的生物信号传导中的作用及其在动脉粥样硬化中的作用。这些结果将是重要的，因为他们被期望提供创新的目标，并提供证据-本发明涉及可用于预防和治疗人类肥胖症的心血管并发症的新型抑制剂的概念。