Triglycerides, Diabetes and Cardiovascular Disease

甘油三酯、糖尿病和心血管疾病项目的总体假设是 特定蛋白-APOC3、ANGPTL3、ANGPTL3驱动的富含甘油三酯的脂蛋白代谢异常 PLTP和LPL-促进高致动脉粥样硬化的残余脂蛋白颗粒在 糖尿病患者，即使是甘油三酯水平正常的患者。残留的脂蛋白颗粒和 高密度脂蛋白相关异常通过改变巨噬细胞增加心血管疾病风险 功能，从而促进动脉粥样硬化的形成，增加糖尿病心血管疾病的风险。 我们认为，与糖尿病相关的心血管疾病(CVD)风险增加可能是 只有增加我们对调节甘油三酯的因素的了解，才能了解、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及其残留物由各种新生和代谢衍生的颗粒组成 大小、蛋白质组成和脂肪含量不同，这使得识别机制变得困难 促进动脉粥样硬化的物质。我们计划通过专注于特定的途径和 并使用独特的分析工具。我们相信，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TRLS如何 而RLP会增加心血管疾病的风险。我们团队在不同方面的专长涉及到整体 本计划项目的假设将确保项目之间的协同和交叉受精，这很可能 以显著推进这一重要而及时的领域的研究。重要的是，RLP和控制 他们可以接受治疗干预。因此，我们相信我们的项目将提供新的见解。 探讨糖尿病心血管疾病的发病机制，并提出新的靶向和预防心血管疾病风险增加的方法 在这个庞大的人口群体中。方案项目赠款由四个项目和三个核心单位组成： 项目1：糖尿病、富含甘油三酯的脂蛋白和晚期动脉粥样硬化 博士，项目负责人 项目2：血管紧张素转换酶3对人类脂肪和葡萄糖代谢的调节-医学博士内森·斯蒂齐尔 博士，项目负责人 项目3：脂解调节和糖尿病受损回归--Ira J.Goldberg，医学博士，项目负责人 项目4：糖尿病患者的脂蛋白和心血管风险--JayW.Heinecke，医学博士，项目负责人 核心A：行政核心--卡琳·E·伯恩菲尔特，博士，核心主管 核心B：蛋白质组学和脂蛋白表征核心-Tomas Vaisar博士，核心董事 核心C：髓系细胞和动脉粥样硬化核心-珍妮·E·坎特博士，核心主任

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