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Project 4: Lipoproteins and CVD risk in diabetes

项目 4：糖尿病中的脂蛋白和 CVD 风险

基本信息

批准号：
10450864
负责人：
JAY W HEINECKE
金额：
$ 43.47万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450864
关键词：
Animals Apolipoprotein A-I Arterial Fatty Streak Arteries Atherosclerosis Biological Assay Biological Markers Cardiac Cardiovascular Diseases Cause of Death Cholesterol Clinical Research Cohort Studies Collaborations Complement Couples Data Defect Diabetes Mellitus Diabetic mouse Event Exhibits Future Generations Genetic Engineering Genetic Polymorphism Goals Heart Diseases Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Human Hypertriglyceridemia Impairment In Vitro Incidence Insulin-Dependent Diabetes Mellitus Lipids Lipolysis Lipoprotein (a)Lipoproteins Low-Density Lipoproteins Mediator of activation protein Mendelian randomization Metabolism Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Patients Persons Phospholipid Transfer Proteins Play Population Production Proteins Regulation Research Research Design Research Personnel Risk Risk Factors Role Severities Testing Triglycerides Type 2 diabetic Very low density lipoprotein analytical method atherogenesis base cardioprotection cardiovascular disorder risk cardiovascular risk factor diabetic diabetic patient experience experimental study glycemic control interest ion mobility lipoprotein cholesterol macrophage mouse model non-diabetic particle programs prospective type I diabetic

项目摘要

Our research program aims to identify modifiable factors that promote atherogenesis by increasing levels of atherogenic lipoproteins and/or by impairing HDL’s ability to remove cholesterol from artery wall macrophages. In contrast to most investigators, we first identify proteins and lipoproteins that predict cardiovascular disease risk (CVD) risk in humans and then perform mechanistic studies in mice based on those results. A major component of this approach has been to devise high-throughput state-of-the-art analytical methods for use in clinical studies. We have a particular interest in diabetic atherosclerotic disease because there are no well- established lipoprotein risk factors in type 1 diabetic patients (T1DM) and because type 2 diabetic patients (T2DM) treated with statins still have a substantial risk for CVD. Our compelling preliminary data suggest that small HDL particles altered by the diabetic milieu strongly predict future CVD events in healthy T1DM patients (n=181, P=0.0008). In parallel, we isolated HDL from 19 T2DM subjects and 20 control subjects and showed that small HDL’s cholesterol efflux capacitya proposed metric of HDL’s cardioprotective effectswas markedly impaired in the T2DM subjects. These observations point to two specific defects in HDL of T1DM and T2DM patients—size and inability to remove cholesterol from the artery wall—that may increase CVD risk. The demonstration that small HDL particles are markedly elevated in healthy T1DM patients who subsequently experience CVD events contradicts the dogma that high levels of HDL are always cardioprotective. A major goal of this proposal is to identify the mechanisms underlying the association of small HDL with CVD. First, we propose to confirm and extend our findings in two large clinical studies of T1DM and T2DM subjects. We also plan to explore the hypothesis that lipolysis of triglyceride-rich lipoproteins couples the generation of highly atherogenic remnant lipoproteins (RLPs) with remodeling of HDL into small, dysfunctional particles. Second, we will use a mouse expressing human APOA1, HDL’s major protein, to test the role of phospholipid transfer protein (PLTP) in the formation of RLPs and small HDL particles in diabetic mice. We base this approach on the demonstration that PLTP drives the generation of both small and large HDL particles in mice, that PLTP increases hepatic production of VLDL (the precursor of RLPs), and that PLTP associates in Mendelian randomization studies with increased CVD risk in concert with increased HDL-cholesterol levels and a larger percentage of small HDL. Importantly, PLTP also predicted incident CVD in our study of T1DM patients. Collectively, our proposed experiments will provide a powerful test of the hypothesis that a high level of small, dysfunctional HDL is a marker, and perhaps a mediator, of increased CVD risk in patients with diabetes.

我们的研究计划旨在确定可改变的因素，促进动脉粥样硬化的水平增加