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.

我们的研究计划旨在通过提高动脉粥样硬化的水平来确定可改变的因素 致动脉粥样硬化脂蛋白和/或通过损害高密度脂蛋白从动脉壁巨噬细胞中清除胆固醇的能力。 与大多数研究人员不同，我们首先识别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制研究。一个专业 该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疾病特别感兴趣，因为没有良好的 确定了 1 型糖尿病患者 (T1DM) 的脂蛋白危险因素，并且因为 2 型糖尿病患者 使用他汀类药物治疗的 (T2DM) 患者仍然存在很大的 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 T1DM 患者未来的 CVD 事件（n=181，P=0.0008）。同时，我们从 19 个 T2DM 中分离出 HDL 受试者和 20 名对照受试者并显示小 HDL 的胆固醇流出能力提出的指标 HDL 的心脏保护作用在 T2DM 受试者中明显受损。这些观察点 T1DM 和 T2DM 患者 HDL 的两个特定缺陷——大小和去除胆固醇的能力 来自动脉壁——这可能会增加 CVD 风险。证明小 HDL 颗粒显着 在随后经历 CVD 事件的健康 T1DM 患者中，该值升高，这与高值这一教条相矛盾。 HDL 水平始终具有心脏保护作用。该提案的一个主要目标是确定机制 小 HDL 与 CVD 之间存在关联。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。我们还计划探索脂肪分解的假设 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 将 HDL 重塑为功能失调的小颗粒。其次，我们将使用表达人类 APOA1 的小鼠， HDL的主要蛋白，测试磷脂转移蛋白（PLTP）在RLP和小颗粒形成中的作用 糖尿病小鼠体内的高密度脂蛋白颗粒。我们将这种方法建立在 PLTP 驱动生成的演示之上 小鼠体内的小和大 HDL 颗粒，PLTP 都会增加肝脏 VLDL 的产生（VLDL 的前体） RLPs），并且在孟德尔随机研究中 PLTP 与 CVD 风险增加相关 HDL 胆固醇水平增加，小 HDL 比例增加。重要的是，PLTP 还预测 我们对 T1DM 患者的研究中发生了 CVD。总的来说，我们提出的实验将提供强有力的测试 假设高水平的小、功能失调的 HDL 是一个标志物，也许是一个介质， 糖尿病患者的 CVD 风险增加。