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

项目概要 高甘油三酯血症（hyperTG）很常见，并且与至少两种重要的医学疾病有因果关系 后果：TG 极度升高时复发性急性胰腺炎和动脉粥样硬化性心血管疾病 各种升高的甘油三酯（TG）的疾病（CVD）。这两者都代表了未满足的医疗需求，因为目前 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对新疗法的需求 减少 TG 以及高甘油三酯和富含甘油三酯脂蛋白 (TRL) 升高的临床后遗症。人类 遗传学研究表明 TRL 与胰腺炎和 CVD 风险存在因果关系，并已确定了一些 潜在的治疗靶点。在这个项目中，我们重点关注经过基因验证的 ApoC-III 和 ApoA-V 并相互调节 LPL 活性，从而影响甘油三酯水平以及胰腺炎和 CVD 的风险。这个 该提案将建立在我们当前资助周期的工作基础上，并将提供有关 ApoA-V 及其的新信息 与 ApoC-III 相互关系，并促进基于 ApoA-V 的治疗策略的发展 减少 TG 和 TRL 升高的临床后果。我们将详细了解 ApoA-V 的结构与功能关系，并更深入地了解 ApoA-V 增强的机制 LPL 并可能减少 VLDL 分泌。这些信息对于告知发展高度相关 以 ApoA-V 为靶点的转化疗法，旨在降低甘油三酯升高和临床后遗症 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.