Structural basis for cardioprotective HDL

心脏保护性 HDL 的结构基础

• 批准号: 10308003
• 负责人: Karin E. Bornfeldt
• 金额: $ 69.12万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308003
• 关键词: ATP binding cassette transporter 1; Adopted; Affect; Agreement; Animal Model; Animals; Apolipoprotein A-I; Apolipoproteins; Atherosclerosis; Binding; Biochemical; C-terminal; Cardiovascular Diseases; Carotid Atherosclerotic Disease; Cell Surface Proteins; Chemicals; Cholesterol; Complement; Complement Activation; Crystallization; Data; Diabetes Mellitus; Docking; Engineering; Enzymes; Face; Foam Cells; Goals; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Human body; Impairment; In Vitro; Innate Immune System; Investigation; Isotope Labeling; Left; Lesion; Lipase; Lipids; Liver; Low Density Lipoprotein Receptor; Mass Spectrum Analysis; Mediating; Molecular; Mus; Mutate; N-terminal; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylcholine-Sterol O-Acyltransferase; Physiological; Plasma; Property; Protein Family; Proteins; Reaction; Regulation of Proteolysis; Research; Resolution; Sodium Chloride; Structure; Techniques; Testing; Type 2 diabetic; adeno-associated viral vector; atherogenesis; cardioprotection; cardiovascular disorder risk; cell type; conformer; crosslink; diabetic; diabetic patient; dimer; heart disease risk; in vivo; insight; macrophage; molecular modeling; monomer; mouse model; non-diabetic; particle; reconstitution; replication factor C; scaffold; simulation; targeted treatment; therapy development

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.

我们的长期目标是建立负责HDL心脏保护功能的结构特征 在人类中，这可能对预测CVD风险和开发HDL靶向药物具有重要意义。 治疗学我们最近发现，载脂蛋白A1（APOA 1），HDL的主要载脂蛋白，可以 假定三种不同的反平行异构体结构，我们称之为旋转异构体。强有力的初步数据表明， 不同的旋转异构体存在于人类中，它们影响HDL的大小和结合不同蛋白质的能力， 具有不同的能力，以促进胆固醇流出巨噬细胞的ABCA 1途径。以确定 APOA 1旋转异构体的生理相关性，因此我们提出了两个具体的目标。 首先，我们将设计Apoa 1-/-小鼠，使其表达突变形式的人APOA 1，从而使HDL选择性地 在体内形成APOA 1的特异性旋转异构体。然后我们将确定不同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、高密度脂蛋白载量和动脉粥样硬化 模型 第二，我们将通过分析有和没有颈动脉粥样硬化的人的HDL来补充我们的动物研究。 动脉粥样硬化性疾病，以及伴有或不伴有糖尿病。我们将确定是否分配特定的 旋转异构体、HDL亚种和HDL蛋白质货物与胆固醇流出能力相关， 与这些受试者的动脉粥样硬化疾病相关或预测动脉粥样硬化疾病。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， 心血管疾病，我们提出的调查HDL的结构特征，与这两个 HDL功能受损和动脉粥样硬化性疾病可以为HDL相关的 具有心脏保护作用但不依赖于HDL胆固醇水平的因素。