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: 9893203
• 负责人: Karin E. Bornfeldt
• 金额: $ 103.78万
• 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/9893203
• 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; 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，近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30%以上的人有糖尿病前期。大约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都明显 增加心血管疾病(CVD)的风险，而且因为CVD事件发生在患者的年轻年龄 对于糖尿病来说，了解糖尿病如何增加心血管疾病风险以及如何预防心血管疾病是至关重要的。 心血管疾病风险增加的患者通常使用他汀类药物来降低低密度脂蛋白胆固醇。然而，即使是 使用他汀类药物治疗，糖尿病患者有残留的心血管风险和更高的心脏病发作发生率和 中风比没有糖尿病的受试者要高。T2 DM和甘油三酯升高患者的这种残余心血管风险 (TGS)与富含甘油三酯的脂蛋白(TRL)的异常代谢有关。然而，甘油三酯水平 在大多数T1 DM患者中，TRL是正常的，目前的教条认为TRL不会导致这些患者发生心血管疾病。 我们假设血浆TGS不能准确反映致动脉粥样硬化残余脂蛋白的水平。 源自极低密度脂蛋白或乳糜粒的颗粒(RLP)，因为RLP和小的VLDL含有的甘油三酯要少得多 而不是TRL。我们已经开发了一种新的方法来定量RLP和小的VLDL。此外，我们的数据 表明血清载脂蛋白C3(APOC3)水平升高可预测T1 DM患者的心血管事件 调整了糖尿病严重程度和其他传统风险因素；这种相关性在患有 正常TGS。APOC3增加TRL和RLP水平。我们以前曾报告过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 抑制巨噬细胞的糖酵解，这反过来又与内质网应激和斑块不稳定性有关。 在接下来的7年里，这个项目将揭示人类心血管疾病风险增加背后的机制，重点是 RLP和APOC3是T1 DM和T2 DM患者的心血管危险因素，TG水平在正常范围。通过 使用我们的糖尿病加速动脉粥样硬化的机械小鼠模型，我们还将阐明糖尿病- 促进早期和晚期动脉粥样硬化的诱导机制。作为这些机械学研究的一部分， 我们将通过单细胞蛋白质组学揭示糖尿病、APOC3和RLP是如何改变病变巨噬细胞的 RNA测序、流式细胞术和功能分析。通过结合关于心血管疾病风险的前瞻性研究， 我们相信，患有糖尿病的人类和我们的糖尿病加速动脉粥样硬化的机械性小鼠模型 我们处于一个极好的位置，可以填补我们在理解如何 糖尿病促进心血管疾病，并确定新的治疗和预防策略。