Structure-Function Analysis of Triglyceride Regulator ApoA-V Using Natural Variants

使用天然变体进行甘油三酯调节剂 ApoA-V 的结构功能分析

• 批准号: 10605242
• 负责人: Daniel James Rader
• 金额: $ 78.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605242
• 关键词: APOA5 gene; Acceleration; Acute; Address; Apolipoproteins A; Apolipoproteins B; Apolipoproteins C; Atherosclerosis; Binding; Binding Proteins; Biochemical; Biological; Biological Assay; Biophysics; Blood; Cardiovascular Diseases; Catabolism; Cells; Chronic; Clinic; Clinical; Coronary Arteriosclerosis; Development; Dose; Effectiveness; Engineering; Fatty acid glycerol esters; Generations; Genetic study; Goals; Grant; Human; Human Genetics; Hypertriglyceridemia; Impairment; Individual; Injections; Investigation; Kinetics; Knockout Mice; Label; Lipid Binding; Lipids; Lipoproteins; Medical; Metabolism; Modeling; Molecular; Mus; Natural Selections; Oral; Pancreatitis; Participant; Plasma; Production; Proteins; Recombinants; Recurrence; Reporting; Risk; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic antibodies; Tracer; Triglycerides; Variant; Very low density lipoprotein; Work; acute pancreatitis; adeno-associated viral vector; cardiovascular disorder risk; gain of function; genetic variant; in vitro Assay; in vivo; insight; lipoprotein lipase; lipoprotein triglyceride; loss of function; novel therapeutics; overexpression; prevent; stable isotope; targeted treatment; therapeutic target; therapy development; tool; translational potential; translational therapeutics

PROJECT SUMMARY Hypertriglyceridemia (hyperTG) is common and is causally associated with at least two important medical consequences: recurrent acute pancreatitis when TGs are extremely elevated and atherosclerotic cardiovascular disease (CVD) across a wide range of elevated TGs. Both of these represent unmet medical needs, as current approaches to reducing TGs are often insufficient in reducing extremely elevated TGs, preventing pancreatitis, and/or reducing cardiovascular disease (CVD) risk. These observations emphasize the need for novel therapies to reduce TGs and the clinical sequelae of hyperTG and elevated triglyceride-rich lipoproteins (TRLs). Human genetics studies indicate that TRLs are causally related to risk of pancreatitis and CVD, and have identified a number of potential therapeutic targets. In this project we focus on ApoC-III and ApoA-V, which are genetically validated and reciprocally modulate LPL activity, thereby influencing triglyceride levels and risk of pancreatitis and CVD. This proposal will build upon our work in the current grant cycle and will provide new information regarding ApoA-V and its reciprocal relationship with ApoC-III, as well as enhance the development of ApoA-V based therapeutic strategies to reduce the clinical consequences of elevated TGs and TRLs. We will derive a detailed understanding of the structure-function relationships of ApoA-V and gain greater insight into the mechanisms by which ApoA-V enhances LPL and possibly reduces VLDL secretion. This information will be highly relevant to informing the development of translational therapies that target ApoA-V with the goal of reducing elevated triglycerides and the clinical sequelae of acute pancreatitis and atherosclerotic CVD.

项目总结 高甘油三酯血症(HyperTG)很常见，至少与两种重要医学疾病有关 后果：当TGS极度升高时复发的急性胰腺炎和动脉粥样硬化的心血管 疾病(CVD)横跨各种升高的TGS。这两项都是目前未得到满足的医疗需求。 降低TGS的方法往往不足以降低极高的TGS，预防胰腺炎， 和/或降低心血管疾病(CVD)风险。这些观察结果强调了新疗法的必要性。 以减少TGS和高甘油三酯及富含甘油三酯的脂蛋白(TRL)升高的临床后遗症。人类 遗传学研究表明，TRL与胰腺炎和心血管疾病的风险有因果关系，并已确定了许多 潜在的治疗靶点。在这个项目中，我们关注的是ApoC-III和ApoA-V，它们是经过基因验证的 并相互调节LPL活性，从而影响甘油三酯水平以及胰腺炎和心血管疾病的风险。这 提案将建立在我们在当前赠款周期中的工作基础上，并将提供关于ApoA-V及其 与载脂蛋白C-III的相互关系以及促进基于载脂蛋白A-V的治疗策略的发展 以减少TGS和TRL升高的临床后果。我们将详细了解 载脂蛋白A-V的结构-功能关系和更深入地了解载脂蛋白A-V增强的机制 LPL并可能减少极低密度脂蛋白的分泌。这一信息将高度相关，为 以载脂蛋白A-V为靶点的转化性治疗，目的是减少升高的甘油三酯和糖尿病的临床后遗症 急性胰腺炎和动脉粥样硬化性心血管疾病。