Role of Plasminogen Activator Inhibitor-1 in Adipose Tissue Dysfunction and Atherosclerosis in Metabolic Syndrome

纤溶酶原激活剂抑制剂 1 在代谢综合征脂肪组织功能障碍和动脉粥样硬化中的作用

基本信息

批准号：
9913573
负责人：
William P Fay
金额：
$ 36.02万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913573
关键词：
Address Adipocytes Adipose tissue Animal Model Animals Antiinflammatory Effect Aorta Arterial Fatty Streak Arteries Atherosclerosis Attenuated Biochemistry Biology Blood Vessels Cardiovascular system Cell Aging Cell physiology Central obesity Cholesterol Closure by clamp Data Development Diabetes Mellitus Diet Disease Drug Targeting Dyslipidemias Effectiveness Energy Metabolism Environment Exercise Family suidae Fibrin Fibrinolysis Functional disorder Goals Heart Homeostasis Human Inflammation Insulin Resistance Isotopes LDL-Receptor Related Protein 1 Lipids Literature Liver Mediating Metabolic Metabolic dysfunction Metabolic syndrome Methods Missouri Molecular Mus Myocardial Infarction Nonesterified Fatty Acids Obesity Pathogenesis Pathologic Pathologic Processes Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Phase I Clinical Trials Plasma Plasma Proteins Plasminogen Activator Inhibitor 1 Plasminogen Inactivators Positioning Attribute Predisposition Property Public Health Research Personnel Resistance Process Risk Role Safety Series Serine Proteinase Inhibitors System Testing Thinness Thrombosis Tissues Triglycerides Universities Urokinase Visceral Weight Gain Work atherogenesis base cardiovascular risk factor cell motility clinical application clinically relevant experience experimental study fatty acid transport glucose metabolism high risk human disease human model improved inhibitor/antagonist insulin mediators insulin sensitivity insulin signaling lipid biosynthesis lipid metabolism lipid transport macrophage monocyte mouse model novel pandemic disease phase I trial preservation prevent protein expression small molecule translational model translational study uptake western diet

项目摘要

Project Summary/Abstract Changes in dietary and exercise patterns have led to a pandemic of the metabolic syndrome, which is characterized by visceral obesity, insulin resistance, dyslipidemia, and a strong predisposition to atherosclerosis. Increased expression of plasminogen activator inhibitor-1 (PAI-1) is also a hallmark of the metabolic syndrome. PAI-1 is a serine protease inhibitor that rapidly inhibits tissue- and urokinase-type plasminogen activators, thereby stabilizing fibrin and promoting thrombosis. PAI-1 is also an important mediator of insulin resistance and cellular processes that drive atherosclerosis development, including vascular cell migration and senescence. Our group has shown that PAI-039, a specific inhibitor of PAI-1, produces significant anti-atherosclerosis, anti-obesity, and anti-inflammatory effects in a murine model of the metabolic syndrome. This work is the first to demonstrate that drug targeting of the fibrinolytic system inhibits atherosclerosis formation. The objectives of this proposal are to define the mechanisms by which PAI-1 inhibitors produce these beneficial effects and determine their safety and efficacy under clinically relevant conditions. It is hypothesized that pharmacological targeting of PAI-1 will 1) inhibit atherosclerosis formation by direct vascular effects, including inhibition of macrophage invasion into plaques, vascular cell senescence, and cholesterol uptake into the arterial wall, 2) inhibit obesity by increasing energy expenditure, uncoupling protein (UCP) expression, and beige adipocyte formation in adipose tissue, and 3) attenuate insulin resistance and pathological fluxes of free fatty acids and cholesterol in the metabolic syndrome. An interdisciplinary team of investigators with extensive experience in vascular biology, obesity, glucose and lipid metabolism, and the biochemistry and pharmacology of PAI-1 has been assembled to carry out this work. The proposed studies will involve PAI-039 and another novel PAI-1 inhibitor, CDE-268. These compounds will be studied in murine models of the metabolic syndrome, as well as in lean mice, using a series of novel and sophisticated methods aimed at defining the mechanisms by which drug targeting of PAI-1 inhibits atherosclerosis, adipose tissue dysfunction, insulin resistance, and dyslipidemia. Ossabaw swine, a highly translational model of the metabolic syndrome and atherosclerosis formation, will also be employed, thus leveraging the outstanding environment at the University of Missouri for studying large animal models of human disease. These studies will determine the efficacy and safety of long-term administration of PAI-1 inhibitors under clinically relevant conditions. The central premise of this proposal is that PAI-1 is a drug target for treating metabolic syndrome and reducing cardiovascular risk. This work has major public health implications, as obesity and atherosclerosis are amongst the most important diseases facing US citizens. Successful completion of these studies will define the pathological functions of PAI-1 in obesity and atherosclerosis and position our team to initiate a phase I clinical trial of pharmacologic PAI-1 inhibition in humans with metabolic syndrome.

项目概要/摘要饮食和运动模式的改变导致了代谢综合征的流行，这是其特征是内脏肥胖、胰岛素抵抗、血脂异常和强烈的易感性动脉粥样硬化。纤溶酶原激活物抑制剂-1 (PAI-1) 表达增加也是代谢综合征。 PAI-1 是一种丝氨酸蛋白酶抑制剂，可快速抑制组织型和尿激酶型纤溶酶原激活剂，从而稳定纤维蛋白并促进血栓形成。 PAI-1也是一个重要的胰岛素抵抗和驱动动脉粥样硬化发展的细胞过程的介质，包括血管细胞迁移和衰老。我们的小组已证明 PAI-039（PAI-1 的一种特异性抑制剂）可产生在小鼠代谢模型中具有显着的抗动脉粥样硬化、抗肥胖和抗炎作用综合症。这项工作首次证明了靶向纤溶系统的药物可抑制动脉粥样硬化的形成。该提案的目标是定义 PAI-1 的机制抑制剂产生这些有益作用并在临床相关条件下确定其安全性和有效性状况。据推测，PAI-1 的药理学靶向将 1) 抑制动脉粥样硬化形成通过直接血管效应，包括抑制巨噬细胞侵入斑块、血管细胞衰老，和胆固醇摄取到动脉壁，2）通过增加能量消耗、解偶联来抑制肥胖蛋白质 (UCP) 表达和脂肪组织中米色脂肪细胞的形成，以及 3) 减弱胰岛素抵抗以及代谢综合征中游离脂肪酸和胆固醇的病理通量。跨学科团队由在血管生物学、肥胖、葡萄糖和脂质代谢方面具有丰富经验的研究人员组成，已组装 PAI-1 的生物化学和药理学来开展这项工作。拟议的研究将涉及 PAI-039 和另一种新型 PAI-1 抑制剂 CDE-268。这些化合物将在小鼠身上进行研究使用一系列新颖而复杂的方法建立代谢综合征模型以及瘦小鼠模型旨在明确 PAI-1 药物靶向抑制动脉粥样硬化、脂肪组织的机制功能障碍、胰岛素抵抗和血脂异常。 Ossabaw猪，一种高度转化的模型代谢综合征和动脉粥样硬化的形成也将被采用，从而利用杰出的密苏里大学研究人类疾病大型动物模型的环境。这些研究将确定临床相关条件下长期服用 PAI-1 抑制剂的有效性和安全性状况。该提案的中心前提是PAI-1是治疗代谢综合征的药物靶点并降低心血管风险。这项工作具有重大的公共卫生影响，因为肥胖和动脉粥样硬化是美国公民面临的最重要的疾病之一。顺利完成这些研究将明确 PAI-1 在肥胖和动脉粥样硬化中的病理功能，并使我们的团队能够启动对患有代谢综合征的人类进行药理学 PAI-1 抑制的 I 期临床试验。