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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.

项目总结/文摘