Triglycerides, Diabetes and Cardiovascular Disease

甘油三酯、糖尿病和心血管疾病

• 批准号: 10450856
• 负责人: Karin E. Bornfeldt
• 金额: $ 236.04万
• 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/10450856
• 关键词: ANGPTL3 gene; Address; Affect; Apolipoproteins; Applications Grants; Area; Atherosclerosis; Cardiovascular Diseases; Chylomicrons; Complement; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Doctor of Philosophy; Ensure; Fertilization; Generations; Genes; Glucose; Goals; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hypertriglyceridemia; Impairment; Inflammatory; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Interruption; Investigation; Knowledge; LDL Cholesterol Lipoproteins; Lesion; Link; Lipids; Lipolysis; Lipoproteins; Low-Density Lipoproteins; Metabolic; Metabolic syndrome; Metabolism; Methods; Myeloid Cells; Nature; New York; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Phospholipid Transfer Proteins; Population; Prevention strategy; Production; Program Research Project Grants; Prospective Studies; Proteins; Proteomics; Regulation; Research; Research Personnel; Residual state; Risk; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Triglyceride Metabolism; Triglycerides; Universities; Very low density lipoprotein; Washington; analytical tool; atherogenesis; atherosclerosis risk; cardiovascular disorder prevention; cardiovascular disorder risk; design; diabetic; diabetic cardiomyopathy; dyslipoproteinemia; effective intervention; fatty liver disease; glucose metabolism; insight; lipid metabolism; lipoprotein lipase; lipoprotein triglyceride; macrophage; mouse model; non-diabetic; novel; novel therapeutics; particle; premature; prevent; programs; synergism

The overall hypothesis of the Triglycerides, Diabetes and Cardiovascular Disease Program Project is that abnormal metabolism of triglyceride-rich lipoproteins driven by specific proteins—APOC3, ANGPTL3, PLTP, and LPL—promotes the accumulation of highly atherogenic remnant lipoprotein particles in patients with diabetes, even in those with normal triglyceride levels. Remnant lipoprotein particles and associated abnormalities in HDL contribute to cardiovascular disease risk by altering macrophage functions, thereby promoting atherogenesis and increasing cardiovascular disease risk in diabetes. We propose that the increased risk of cardiovascular disease (CVD) associated with diabetes can be understood, prevented, and treated only by increasing our knowledge of the factors that regulate triglyceride- rich lipoproteins (TRLs) and their remnant lipoprotein particles (RLPs) and associated macrophage phenotypes. TRLs and their remnants comprise a great variety of nascent and metabolically derived particles differing in size, protein composition, and lipid content, which has made it difficult to identify the mechanisms that promote atherosclerosis. We plan to address this complexity by focusing on specific pathways and proteins and by using unique analytical tools. We believe that a highly interactive and interdisciplinary group of investigators with extensive expertise in this area, such as ours, is needed to answer the question of how TRLs and RLPs promote CVD risk. The expertise of our team in different aspects pertaining to the overall hypotheses of this Program Project will ensure synergy and cross-fertilization between Projects, which is likely to markedly advance research in this important and timely area. Importantly, the RLPs and proteins that control them are amenable to therapeutic intervention. We therefore believe that our projects will provide new insights into the pathogenesis of CVD in diabetes and suggest new ways to target and prevent the increased CVD risk in this large population. The Program Project Grant consists of four Projects and three Core units:  Project 1: Diabetes, triglyceride-rich lipoproteins, and advanced atherosclerosis – Karin E. Bornfeldt, PhD, Project Leader  Project 2: Regulation of lipid and glucose metabolism by ANGPTL3 in humans – Nathan Stitziel, MD, PhD, Project Leader  Project 3: Lipolysis regulation and diabetes-impaired regression – Ira J. Goldberg, MD, Project Leader  Project 4: Lipoproteins and CVD risk in diabetes – Jay W. Heinecke, MD, Project Leader  Core A: Administrative Core – Karin E. Bornfeldt, PhD, Core Director  Core B: Proteomics and lipoprotein characterization core – Tomas Vaisar, PhD, Core Director  Core C: Myeloid cell and atherosclerosis core – Jenny E. Kanter, PhD, Core Director

甘油三酯、糖尿病和心血管疾病项目的总体假设是， 由特定蛋白-APOC 3，ANGPTL 3， PLTP和LPL-促进高致动脉粥样硬化性残余脂蛋白颗粒在 糖尿病患者，即使是甘油三酯水平正常的患者。残余脂蛋白颗粒和 HDL相关异常通过改变巨噬细胞 功能，从而促进动脉粥样硬化和增加糖尿病心血管疾病的风险。 我们认为，糖尿病相关的心血管疾病（CVD）风险增加， 只有通过增加我们对调节甘油三酯的因素的了解，才能理解，预防和治疗- 富含脂蛋白（TRL）及其残余脂蛋白颗粒（RLP）和相关巨噬细胞 表型TRL及其残余物包括各种各样的新生和代谢衍生的颗粒 不同的大小，蛋白质组成和脂质含量，这使得难以确定的机制， 会促进动脉粥样硬化我们计划通过专注于特定途径来解决这种复杂性， 蛋白质和使用独特的分析工具。我们认为，一个高度互动和跨学科的小组， 需要像我们这样在这一领域具有广泛专业知识的调查人员来回答TRL如何 RLP会增加CVD风险。我们的团队在不同方面的专业知识与整体 该计划项目的假设将确保项目之间的协同作用和交叉施肥，这是可能的 在这一重要而及时的领域显著推进研究。重要的是，RLP和蛋白质控制 它们易于接受治疗干预。因此，我们相信，我们的项目将提供新的见解， 研究糖尿病心血管疾病的发病机制，并提出新的方法来靶向和预防心血管疾病风险的增加。 在这个庞大的人口。该计划项目赠款包括四个项目和三个核心单元： 糖尿病、富含磷脂酰肌醇的脂蛋白和晚期动脉粥样硬化。伯恩费尔特， 博士，项目负责人 研究项目2：ANGPTL 3在人体中对脂质和葡萄糖代谢的调节- Nathan Stitterman，MD， 博士，项目负责人 项目3：脂解调节和糖尿病受损的回归-伊拉J.戈德堡，医学博士，项目负责人 糖尿病患者的脂蛋白和心血管疾病风险- Jay W. Heinecke，MD，项目负责人 核心A：行政核心- Karin E。Bornfeldt，PhD，核心总监 核心B：蛋白质组学和脂蛋白表征核心- Tomas Vaisar，PhD，核心总监 核心C：髓样细胞和动脉粥样硬化核心- Jenny E. Kanter，PhD，核心总监