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（T1DM 或 T2DM），超过 30% 患有糖尿病前期。大约 140 万儿童和成人 患有 T1DM。因为糖尿病的患病率持续上升，因为 T1DM 和 T2DM 都显着 增加心血管疾病 (CVD) 的风险，并且由于 CVD 事件发生在患者较年轻的年龄 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低密度脂蛋白胆固醇。然而，即使 使用他汀类药物治疗时，糖尿病患者存在残余 CVD 风险，并且心脏病发作的发生率更高 中风的发生率高于未患糖尿病的受试者。 T2DM 和甘油三酯升高患者的残余 CVD 风险 （TG）与富含甘油三酯的脂蛋白（TRL）的异常代谢有关。然而，TG 水平 大多数 T1DM 患者的 TRL 正常，目前的教条认为 TRL 不会增加这些患者的 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 源自 VLDL 或乳糜微粒的颗粒 (RLP)，因为 RLP 和小 VLDL 含有的 TG 少得多 比 TRL 更重要。我们开发了一种新方法来量化 RLP 和小 VLDL。此外，我们的数据 表明血清载脂蛋白 C3 (APOC3) 水平升高可预测 1 型糖尿病患者的 CVD 事件 根据糖尿病严重程度和其他传统危险因素进行调整；这种相关性是在受试者中发现的 正常TG。 APOC3 增加 TRL 和 RLP 的水平。我们之前曾报道过 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 巨噬细胞糖酵解的抑制，这反过来又与内质网应激和斑块不稳定有关。 在接下来的 7 年内，该项目将揭示人类 CVD 风险增加背后的机制，重点关注 RLPs 和 APOC3 作为 T1DM 和 T2DM 患者的 CVD 危险因素，并且 TG 水平在正常范围内。经过 使用我们的糖尿病加速动脉粥样硬化机制小鼠模型，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。作为这些机制研究的一部分， 我们将通过蛋白质组学、单细胞研究揭示糖尿病、APOC3 和 RLP 如何改变病变巨噬细胞 RNA 测序、流式细胞术和功能测定。通过结合 CVD 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小鼠模型 我们处于非常有利的位置，可以填补我们对如何理解这一问题的重要且具有临床意义的空白。 糖尿病促进心血管疾病并确定新的治疗和预防策略。