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

项目摘要 高甘油三酯血症（hyperTG）很常见，与至少两种重要的医学疾病有因果关系。 结果：当TG极度升高和动脉粥样硬化性心血管疾病时， 疾病（CVD）在广泛的TG升高。这两项都代表了未满足的医疗需求， 降低TG的方法通常不足以降低极高的TG，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 降低TG和高TG临床后遗症以及富含甘油三酯的脂蛋白（TRL）升高。人类 遗传学研究表明TRL与胰腺炎和CVD的风险存在因果关系， 潜在的治疗靶点在这个项目中，我们专注于ApoC-III和ApoA-V，这是基因验证 和甘油三酯调节LPL活性，从而影响甘油三酯水平和胰腺炎和CVD的风险。这 该提案将建立在我们在当前资助周期的工作基础上，并将提供有关ApoA-V及其 与ApoC-III的相互关系，以及促进基于ApoA-V的治疗策略的开发 以减少TG和TRL升高的临床后果。我们将详细了解 ApoA-V的结构-功能关系，并更深入地了解ApoA-V增强 LPL和可能减少VLDL分泌。这一信息将高度相关的通知发展， 靶向ApoA-V的转化疗法，目的是降低甘油三酯升高和 急性胰腺炎和动脉粥样硬化性CVD。

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.