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 靶向具有重要意义 疗法。我们最近表明，HDL 的主要载脂蛋白载脂蛋白 A1 (APOA1) 可以 假设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 人类体内存在不同的旋转异构体，它们会影响 HDL 的大小和结合不同蛋白质的能力，并且 具有通过 ABCA1 途径促进巨噬细胞胆固醇流出的不同能力。确定 鉴于 APOA1 旋转异构体的生理相关性，我们因此提出了两个具体目标。 首先，我们将改造 Apoa1-/- 小鼠，使其表达人类 APOA1 的突变形式，从而导致 HDL 选择性地 在体内形成 APOA1 的特异性旋转异构体。然后我们将确定不同旋转异构体对 HDL 的影响 LDL受体缺陷小鼠的胆固醇流出能力、HDL大小、HDL蛋白货物和动脉粥样硬化 模型。 其次，我们将通过分析有或没有颈动脉的人类 HDL 来补充我们的动物研究 动脉粥样硬化疾病，以及患有或不患有糖尿病。我们将确定是否分配具体的 旋转异构体、HDL 亚种和 HDL 蛋白货物与胆固醇流出能力相关，以及它们是否 与这些受试者的动脉粥样硬化疾病相关或预测。因为初步研究表明HDL 糖尿病患者的胆固醇流出能力受损，糖尿病患者的风险大大增加 心血管疾病的研究中，我们提出了对与心血管疾病相关的 HDL 结构特征的研究 HDL 功能受损和动脉粥样硬化疾病可以为 HDL 相关性提供重要见解 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素。