Structural basis for cardioprotective HDL

心脏保护性 HDL 的结构基础

• 批准号: 10523119
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523119
• 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; 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; Isomerism; Isotope Labeling; Lecithin; Left; Lesion; Lipase; Lipids; Liver; Low Density Lipoprotein Receptor; Macrophage; Mass Spectrum Analysis; Mediating; 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; Sterol O-Acyltransferase; Structure; Study models; 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; molecular dynamics; molecular modeling; monomer; mouse model; non-diabetic; particle; reconstitution; replication factor C; risk prediction; scaffold; 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风险和发展为HDL的重要意义 治疗。我们最近表明，HDL的主要载脂蛋白可以 假设三个不同的反平行等异构结构，我们称为旋转器。强大的初步数据表明 人类中存在不同的旋转植物，并且它们会影响HDL的大小和结合不同蛋白质的能力，并且 通过ABCA1途径从巨噬细胞中促进胆固醇外排具有不同的能力。确定 因此，我们提出了两个具体的目标。 首先，我们将设计apoa1 - / - 小鼠表达突变形式的人apoa1，导致HDL有选择地 形成体内apoA1的特定旋转剂。然后，我们将确定不同的旋转器对HDL的影响 LDL受体缺陷小鼠的胆固醇外排能力，HDL尺寸，HDL蛋白货物和动脉粥样硬化 型号。 其次，我们将通过有或没有颈动脉的人类进行分析来完成动物研究 动脉粥样硬化疾病，有和没有糖尿病。我们将确定特定的分布是否 Rotamers，HDL亚种和HDL蛋白货物与胆固醇外排的能力以及它们是否相关 在这些受试者中与或预测动脉粥样硬化疾病。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 在心血管疾病中，我们提出的对HDL结构特征的调查 HDL功能受损和动脉粥样硬化疾病可以为HDL相关的重要见解 心脏保护性但与HDL胆固醇水平无关的因素。

项目成果

Adipocyte phosphatidylinositol biosynthesis via the Lands cycle protects against insulin resistance.

• DOI: 10.1016/j.jlr.2023.100383
• 发表时间: 2023-06
• 期刊: JOURNAL OF LIPID RESEARCH
• 影响因子: 6.5
• 作者: Bornfeldt, Karin E.

Integrative Multiomics Approaches for Discovery of New Drug Targets for Cardiovascular Disease.

• DOI: 10.1161/circulationaha.121.054900
• 发表时间: 2021-06-22
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Reilly MP;Bornfeldt KE
• 通讯作者: Bornfeldt KE

Apolipoprotein C3: form begets function.

• DOI: 10.1016/j.jlr.2023.100475
• 发表时间: 2024-01
• 期刊: JOURNAL OF LIPID RESEARCH
• 影响因子: 6.5
• 作者: Bornfeldt, Karin E.