Project 4: Lipoproteins and CVD risk in diabetes

项目 4：糖尿病中的脂蛋白和 CVD 风险

• 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
• 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

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.

我们的研究项目旨在通过增加动脉粥样硬化的水平来确定促进动脉粥样硬化形成的可改变因素。 致动脉粥样硬化脂蛋白和/或损害HDL从动脉壁巨噬细胞中去除胆固醇的能力。 与大多数研究者不同，我们首先确定预测心血管疾病的蛋白质和脂蛋白 风险（CVD）的风险，然后根据这些结果在小鼠中进行机制研究。一个主要 这种方法的一个组成部分是设计高通量的最先进的分析方法，用于 临床研究。我们对糖尿病动脉粥样硬化性疾病特别感兴趣，因为没有很好的- 在1型糖尿病患者（T1 DM）和2型糖尿病患者中， 接受他汀类药物治疗的T2 DM患者仍有相当大的CVD风险。 我们令人信服的初步数据表明，糖尿病环境改变的小HDL颗粒强烈预测 健康T1 DM患者未来的CVD事件（n=181，P=0.0008）。同时，我们从19例T2 DM患者中分离出HDL， 受试者和20名对照受试者，并表明小HDL的胆固醇流出能力是一个建议的指标， HDL的心脏保护作用在T2 DM受试者中明显受损。这些观察表明， T1 DM和T2 DM患者HDL的两个特定缺陷-尺寸和无法清除胆固醇 这可能会增加心血管疾病的风险。小的HDL颗粒明显 在随后发生CVD事件的健康T1 DM患者中升高，这与高血糖的教条相矛盾。 高密度脂蛋白的水平总是对心脏有保护作用。该提案的一个主要目标是确定 小HDL与CVD的相关性。首先，我们建议确认和扩展我们的发现， 两项针对T1 DM和T2 DM受试者的大型临床研究。我们还计划探讨脂肪分解的假设， 富含甘油三酯的脂蛋白将高度致动脉粥样硬化的残余脂蛋白（RLP）的产生与 HDL重塑成功能失调的小颗粒。其次，我们将使用表达人APOA 1的小鼠， HDL的主要蛋白质，以测试磷脂转移蛋白（PLTP）在形成RLP和小 糖尿病小鼠中的HDL颗粒。我们基于这种方法的示范，PLTP驱动的一代， 无论是小的和大的HDL颗粒在小鼠中，PLTP增加肝脏生产的VLDL（前体的 在孟德尔随机化研究中，PLTP与CVD风险增加相关， 高密度脂蛋白胆固醇水平增加和小高密度脂蛋白的比例较大。重要的是，PLTP还预测 在我们的T1 DM患者研究中，总的来说，我们提出的实验将提供一个强大的测试， 假设高水平的小，功能失调的HDL是一个标志，也许是一个中介， 糖尿病患者心血管疾病风险增加。