Triglycerides, Diabetes and Cardiovascular Disease

甘油三酯、糖尿病和心血管疾病

• 批准号: 10642739
• 负责人: Karin E. Bornfeldt
• 金额: $ 239.02万
• 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/10642739
• 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; Macrophage; Metabolic; Metabolic syndrome; Metabolism; Methods; Myeloid Cells; Nature; New York; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Patients; Phenotype; Phospholipid Transfer Proteins; Population; Prevention strategy; Production; Productivity; Program Research Project Grants; Prospective Studies; Proteins; Proteomics; Regulation; Research; Research Personnel; Residual state; Risk; Testing; Therapeutic Agents; Therapeutic Intervention; 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; mouse model; non-diabetic; novel; novel therapeutics; particle; pharmacologic; 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

甘油三酸酯，糖尿病和心血管疾病计划项目的总体假设是 由特定蛋白驱动的富含甘油三酸酯的脂蛋白的异常代谢-APOC3，ANGPTL3， PLTP和LPL-促进高度动脉粥样硬化脂蛋白颗粒在中的积累 糖尿病患者，即使在甘油三酸酯水平正常的患者中。残留的脂蛋白颗粒和 HDL的相关异常通过改变巨噬细胞而导致心血管疾病的风险 功能，从而促进糖尿病的动脉粥样硬化和增加心血管疾病风险。 我们建议与糖尿病有关的心血管疾病（CVD）的风险增加可能是 仅通过增加我们对调节甘油三酸酯的因素的了解，理解，预防和治疗 富脂蛋白（TRL）及其残留脂蛋白颗粒（RLP）和相关的巨噬细胞 表型。 TRL及其残余物包含各种新生和代谢衍生的颗粒 大小，蛋白质成分和脂质含量的不同，这使得难以识别机制 促进动脉粥样硬化。我们计划通过专注于特定途径和 蛋白质并使用独特的分析工具。我们认为，一个高度互动和跨学科的群体 需要在该领域（例如我们的）中具有广泛专业知识的调查人员来回答TRL的问题 RLP促进CVD风险。我们团队的专家在与整体有关的不同方面 该计划项目的假设将确保项目之间的协同作用和交叉利用，这很可能 在这个重要及时的领域中明显提高研究。重要的是，控制的RLP和蛋白质 它们适合治疗干预。因此，我们认为我们的项目将提供新的见解 进入糖尿病中CVD的发病机理，并提出新的靶向和防止CVD风险的方法 在这个大量人口中。计划项目赠款由四个项目和三个核心单位组成： 项目1：糖尿病，富含甘油三酸酯的脂蛋白和高级动脉粥样硬化 - Karin E. Bornfeldt， 博士，项目负责人 项目2：Angptl3在人类中对脂质和葡萄糖代谢的调节 - 医学博士Nathan Stitziel， 博士，项目负责人 项目3：脂解调节和糖尿病障碍回归 - Ira J. Goldberg，医学博士，项目负责人 项目4：糖尿病中的脂蛋白和CVD风险 - Jay W. Heinecke，医学博士，项目负责人 核心A：行政核心 - Karin E. Bornfeldt，PhD，核心主任 核心B：蛋白质组学和脂蛋白表征核心 - 托马斯·韦萨尔（Tomas Vaisar）博士，核心主任 核心C：髓样细胞和动脉粥样硬化核心 - Jenny E. Kanter博士，核心主任

项目成果

ABCA1 is an extracellular phospholipid translocase.

ABCA1 是一种细胞外磷脂转位酶。

• DOI: 10.1038/s41467-022-32437-3
• 发表时间: 2022-08-16
• 期刊: Nature communications
• 影响因子: 16.6

Size matters: HDL particle populations and the risk of infection.

大小很重要：HDL 颗粒数量和感染风险。

• DOI: 10.1038/s41569-023-00844-8
• 发表时间: 2023
• 期刊: Nature reviews. Cardiology
• 作者: Heinecke,JayW;Davidson,WSean
• 通讯作者: Davidson,WSean

Addressing dyslipidemic risk beyond LDL-cholesterol.

• DOI: 10.1172/jci148559
• 发表时间: 2022-01-04
• 期刊: The Journal of clinical investigation
• 作者: Tall AR;Thomas DG;Gonzalez-Cabodevilla AG;Goldberg IJ
• 通讯作者: Goldberg IJ

Emerging Concepts of Vascular Cell Clonal Expansion in Atherosclerosis.

• DOI: 10.1161/atvbaha.121.316093
• 发表时间: 2022-03
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Misra A;Rehan R;Lin A;Patel S;Fisher EA
• 通讯作者: Fisher EA