Structural basis for cardioprotective HDL

我们的长期目标是建立负责高密度脂蛋白心脏保护功能的结构特征 在人类中，这可能对预测心血管疾病风险和开发高密度脂蛋白靶向具有重要意义 治疗学。我们最近发现，高密度脂蛋白的主要载脂蛋白ApoA1(APOA1)可以 假设有三种不同的反平行异构体结构，我们称之为旋转异构体。强劲的初步数据表明， 不同的旋转体存在于人类中，它们影响高密度脂蛋白的大小和结合不同蛋白质的能力，以及 通过ABCA1途径促进巨噬细胞胆固醇外流的能力不同。要确定 为了研究APOA1旋转异构体的生理相关性，我们提出了两个具体的目标。 首先，我们将改造ApoA1-/-小鼠表达人类APOA1的突变形式，这种突变形式会导致高密度脂蛋白选择性地 在体内形成APOA1的特异性旋转体。然后我们将确定不同的旋转异构体对高密度脂蛋白的影响 低密度脂蛋白受体缺陷小鼠的胆固醇流出能力、高密度脂蛋白大小、高密度脂蛋白含量与动脉粥样硬化 模特们。 其次，我们将通过分析有无颈动脉的人类高密度脂蛋白来补充我们的动物研究。 动脉粥样硬化性疾病，并伴有和不伴有糖尿病。我们将确定是否分发特定的 旋转异构体、高密度脂蛋白亚型和高密度脂蛋白与胆固醇流出能力相关，以及它们是否 与这些受试者中的动脉粥样硬化性疾病相关或预测。因为初步研究表明，高密度脂蛋白 的糖尿病患者胆固醇流出能力受损，糖尿病患者的风险大大增加。 对于心血管疾病，我们建议对与这两种疾病相关的高密度脂蛋白结构特征进行研究 高密度脂蛋白功能受损和动脉粥样硬化性疾病可以为高密度脂蛋白相关的研究提供重要的见解 具有心脏保护作用但与高密度脂蛋白胆固醇水平无关的因子。

Our long-term goal is to establish the structural features responsible for the cardioprotective functions of HDL in humans, which may have important implications for predicting CVD risk and developing HDL-targeted therapeutics. We have recently shown that apolipoprotein A1 (APOA1), HDL’s major apolipoprotein, can assume three different antiparallel isomeric structures we term rotamers. Strong preliminary data suggests that the different rotamers exist in humans, and that they affect HDL size and ability to bind different proteins, and have different abilities to promote cholesterol efflux from macrophages by the ABCA1 pathway. To determine the physiological relevance of the APOA1 rotamers, we therefore propose two specific aims. First, we will engineer Apoa1-/- mice to express mutated forms of human APOA1 that cause HDL to selectively form specific rotamers of APOA1 in vivo. We will then determine the impact of the different rotamers on HDL cholesterol efflux capacity, HDL size, HDL protein cargo, and atherosclerosis in LDL receptor-deficient mouse models. Second, we will complement our animal studies with analyses of HDLs of humans with and without carotid atherosclerotic disease, and with and without diabetes. We will determine whether the distribution of specific rotamers, HDL subspecies, and HDL protein cargo associate with cholesterol efflux capacity and whether they associate with or predict atherosclerotic disease in these subjects. Because preliminary studies show that HDL of diabetic patients have impaired cholesterol efflux capacity, and diabetic patients are at greatly increased risk of cardiovascular disease, our proposed investigation of the structural features of HDL that associate with both impaired HDL function and atherosclerotic disease could provide important insights into HDL-associated factors that are cardioprotective but are independent of HDL cholesterol levels.