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: 8820510
• 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/8820510
• 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; Lysophospholipids; 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; alkylglycerophosphoethanolamine phosphodiesterase; 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; public health relevance; 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严重的健康负担。对 2000 年在 VA 医疗中心接受护理的近 200 万退伍军人进行的分析表明，约 68% 的人超重，约 37% 的人肥胖。与肥胖相关的医疗费用给退伍军人管理局的医疗保健系统带来压力。肥胖是心血管疾病（CVD）和中风的既定危险因素，肥胖引起的心血管并发症是退伍军人潜在可预防死亡的主要原因。除了导致传统的CVD危险因素之外，肥胖的特征还在于慢性亚急性炎症状态，巨噬细胞浸润脂肪以及脂肪组织产生炎症介质。发炎的脂肪组织可能独特地促进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确定预防和治疗相关心血管疾病的新策略。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 负责产生细胞外的生物活性溶血磷脂酸 (LPA)，这是一种生物活性脂质，以生理相关水平存在于血浆和其他生物液体中，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通透性的影响，我们提出了中心假设，即 ATX 调节的信号通路有助于肥胖相关炎症和动脉粥样硬化的发展。我们将使用最先进的遗传和药理学方法来测试我们的中心假设，以实现两个特定目标。在目标一中，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，我们将确定脂肪来源的 ATX 在动脉粥样硬化发展中的作用。这笔赠款的目的是提供一个工具来解决溶血脂信号传导领域一个尚未解决的主要问题，即脂肪源性 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。这些结果将是意义重大的，因为它们预计将提供创新靶标并为可用于预防和治疗人类肥胖心血管并发症的新型抑制剂提供概念验证。