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：
10642754
负责人：
JAY W HEINECKE
金额：
$ 44.32万
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/10642754
关键词：
Acceleration Animals Apolipoprotein A-I Arterial Fatty Streak Arteries Atherosclerosis Biological Assay Biological Markers Calibration 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 Lipids Lipolysis Lipoprotein (a)Lipoproteins Low-Density Lipoproteins Macrophage Mediator 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 disorder risk experience experimental study glycemic control interest ion mobility 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修改的因素，通过增加水平来促进动脉粥样硬化动脉粥样硬化脂蛋白和/或通过损害HDL从动脉壁巨噬细胞中去除胆固醇的能力。与大多数研究人员相反，我们首先鉴定预测心血管疾病的蛋白质和脂蛋白人类的风险（CVD）风险，然后根据这些结果在小鼠中进行机械研究。专业这种方法的组成部分是设计高通量的最先进的分析方法临床研究。我们对糖尿病动脉粥样硬化疾病特别感兴趣，因为没有很好的在1型糖尿病患者（T1DM）和2型糖尿病患者中，已建立的脂蛋白危险因素（T2DM）用他汀类药物治疗的CVD仍然存在很大的风险。我们引人注目的初步数据表明，由糖尿病环境改变的小型HDL颗粒强烈预测健康T1DM患者的未来CVD事件（n = 181，p = 0.0008）。同时，我们从19 T2DM中分离出HDL 受试者和20个对照受试者，表明小型HDL的胆固醇外排容量a提议的度量 T2DM受试者中HDL的心脏保护作用显着受损。这些观察点 HDL T1DM和T2DM患者的两个特定缺陷 - 大小和无法去除胆固醇从动脉壁上增加CVD风险。小型HDL颗粒显着的证明随后经历CVD事件的健康T1DM患者的提升与教条相矛盾 HDL的水平始终是心脏保护性的。该提议的主要目标是确定机制小型HDL与CVD的关联的基础。首先，我们建议确认并扩展我们的发现 T1DM和T2DM受试者的两项大型临床研究。我们还计划探讨以下假设富含甘油三酸酯的脂蛋白伴侣与高度动脉粥样硬化脂蛋白（RLP）的产生将HDL重塑为小功能失调的颗粒。其次，我们将使用表达人apoa1的鼠标， HDL的主要蛋白质，以测试磷脂转移蛋白（PLTP）在RLP和小的形成中的作用糖尿病小鼠中的HDL颗粒。我们以PLTP驱动产生的演示为基础小鼠中的小型和大型HDL颗粒都增加了PLTP的增加VLDL的肝产生（ RLP），以及在Mendelian随机研究中与CVD风险增加的同伴 HDL-胆固醇水平升高和小型HDL的比例较大。重要的是，PLTP还预测了我们对T1DM患者的研究中的事件CVD。总的来说，我们提出的实验将提供强大的测试假设高水平的小型功能失调的HDL是标记，也许是中介者糖尿病患者的CVD风险增加。