Identifying new strategies for prevention of cardiovascular complications of diabetes

确定预防糖尿病心血管并发症的新策略

• 批准号: 10395427
• 负责人: Karin E. Bornfeldt
• 金额: $ 101.64万
• 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: 2020-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10395427
• 关键词: Adult; Age; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Child; Chylomicrons; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Diabetic mouse; Event; Flow Cytometry; Glycolysis; Goals; Health; Human; Hypertriglyceridemia; Incidence; Insulin-Dependent Diabetes Mellitus; LDL Cholesterol Lipoproteins; Lesion; Link; Lipoproteins; Methods; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Patients; Persons; Plasma; Population; Positioning Attribute; Prediabetes syndrome; Prevalence; Prevention strategy; Prospective Studies; Proteomics; Reporting; Residual state; Risk Factors; Serum; Severities; Stroke; Time; Triglyceride Metabolism; Triglycerides; Very low density lipoprotein; cardiovascular disorder risk; cardiovascular risk factor; clinically significant; endoplasmic reticulum stress; macrophage; novel; particle; prevent; single-cell RNA sequencing; targeted treatment; treatment strategy

Currently, almost 10% of the US population (over 30 million people) suffer from type 1 or type 2 diabetes mellitus (T1DM or T2DM) and more than 30% have pre-diabetes. Approximately 1.4 million children and adults have T1DM. Because the prevalence of diabetes continues to rise, because both T1DM and T2DM markedly increase the risk of cardiovascular disease (CVD), and because CVD events occur at younger ages in patients with diabetes, it is critical to understand how diabetes increases CVD risk and how CVD can be prevented. Patients with increased CVD risk are generally treated with statins to lower LDL cholesterol. However, even with statin treatment, patients with diabetes have residual CVD risk and a greater incidence of heart attack and stroke than subjects without diabetes. This residual CVD risk in patients with T2DM and elevated triglycerides (TGs) has been linked to abnormal metabolism of triglyceride-rich lipoproteins (TRLs). However, TG levels are normal in most T1DM patients, and current dogma maintains that TRLs do not drive CVD risk in these patients. We hypothesize that plasma TGs do not accurately reflect levels of the atherogenic remnant lipoprotein particles (RLPs) derived from VLDL or chylomicrons because RLPs and small VLDL contain much less TG than do TRLs. We have developed a new method to quantify RLPs and small VLDL. Furthermore, our data show that elevated serum apolipoprotein C3 (APOC3) levels predict CVD events in subjects with T1DM when adjusted for diabetes severity and other traditional risk factors; this correlation was found in subjects with normal TGs. APOC3 increases levels of TRLs and RLPs. We have previously reported that TRLs contribute to atherosclerotic plaque instability in mouse models of diabetes. We have also found that diabetes leads to suppression of glycolysis in macrophages, and that this in turn is linked to ER stress and plaque instability. During the next 7 years, this project will reveal mechanisms behind increased CVD risk in humans, focusing on RLPs and APOC3 as CVD risk factors in patients with T1DM and T2DM and TG levels in the normal range. By using our mechanistic mouse models of diabetes-accelerated atherosclerosis, we will also clarify the diabetes- induced mechanisms that promote early and advanced atherosclerosis. As part of these mechanistic studies, we will reveal how diabetes, APOC3 and RLPs alter lesion macrophages, by using proteomics, single cell RNA-sequencing, flow cytometry, and functional assays. By combining prospective studies on CVD risk in humans with diabetes and our mechanistic mouse models of diabetes-accelerated atherosclerosis, we believe we are in an excellent position to fill an important and clinically significant gap in our understanding of how diabetes promotes CVD and to identify new treatment and prevention strategies.

目前，几乎10%的美国人口（超过3000万人）患有1型或2型糖尿病 糖尿病（T1 DM或T2 DM）和超过30%的糖尿病前期。约140万儿童和成人 患有T1 DM。因为糖尿病的患病率持续上升，因为T1 DM和T2 DM都显著增加， 增加心血管疾病（CVD）的风险，并且因为CVD事件发生在患者的年轻年龄 对于糖尿病，了解糖尿病如何增加CVD风险以及如何预防CVD至关重要。 CVD风险增加的患者通常使用他汀类药物治疗以降低LDL胆固醇。但即使 使用他汀类药物治疗，糖尿病患者有残余的CVD风险和更高的心脏病发作发生率， 糖尿病患者比非糖尿病患者更容易患中风。甘油三酯升高的T2 DM患者的剩余CVD风险 (TGs)与富含甘油三酯的脂蛋白（TRL）的异常代谢有关。然而，TG水平 TRL在大多数T1 DM患者中是正常的，目前的教条认为TRL不会导致这些患者的CVD风险。 我们假设血浆TG不能准确反映致动脉粥样硬化残余脂蛋白的水平， 来自VLDL或乳糜微粒的颗粒（RLP），因为RLP和小VLDL含有更少的TG 而不是TRL我们已经开发了一种新的方法来量化RLP和小VLDL。此外，我们的数据 表明血清载脂蛋白C3（APOC 3）水平升高可预测T1 DM受试者的CVD事件， 调整糖尿病严重程度和其他传统风险因素;这种相关性在以下受试者中发现 TG正常。APOC 3增加TRL和RLP的水平。我们以前曾报道过TRL有助于 糖尿病小鼠模型中动脉粥样硬化斑块的不稳定性。我们还发现糖尿病会导致 抑制巨噬细胞中的糖酵解，这反过来又与ER应激和斑块不稳定性有关。 在接下来的7年里，该项目将揭示人类CVD风险增加背后的机制，重点是 RLP和APOC 3作为T1 DM和T2 DM患者的CVD危险因素，且TG水平在正常范围内。通过 使用我们的糖尿病加速动脉粥样硬化的机制小鼠模型，我们还将阐明糖尿病- 诱导机制，促进早期和晚期动脉粥样硬化。作为这些机制研究的一部分， 我们将揭示糖尿病，APOC 3和RLP如何改变病变巨噬细胞，通过使用蛋白质组学，单细胞， RNA测序、流式细胞术和功能测定。通过结合前瞻性研究， 糖尿病患者和我们的糖尿病加速动脉粥样硬化的机制小鼠模型，我们相信， 我们正处于一个很好的位置，以填补一个重要的和临床意义的差距，我们的理解是如何 糖尿病促进心血管疾病，并确定新的治疗和预防策略。