Associations Among Apolipoprotein A1 Structural Variants and High-Density Lipoprotein Function

载脂蛋白 A1 结构变异与高密度脂蛋白功能之间的关联

• 批准号: 9538826
• 负责人: John Thomas Wilkins
• 金额: $ 16.56万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9538826
• 关键词: Advisory Committees; Alleles; Alternative Splicing; Apolipoprotein A-I; Apolipoproteins; Appointment; Atherosclerosis; Biochemical; Biochemical Pathway; Biochemical Process; Bioinformatics; Biological Assay; Biology; Biometry; Cardiology; Cardiovascular Diseases; Cholesterol; Clinical; Clinical Research; Complex; Coronary Artery Risk Development in Young Adults Study; Data; Development; Disease; Disease Outcome; Drug Targeting; Enzymes; Epidemiologist; Epidemiology; Evaluation; Grant; Health; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Imaging technology; Incidence; Individual; Individual Differences; K-Series Research Career Programs; Laboratories; Lead; Life Cycle Stages; Link; Lipids; Literature; Liver; Measures; Mediating; Mediator of activation protein; Mentorship; Methods; Methylation; Molecular; Outpatients; Oxides; Participant; Patients; Pattern; Peripheral; Pharmaceutical Technology; Pharmacologic Substance; Phospholipids; Platelet Factor 4; Post-Translational Protein Processing; Preventive Medicine; Productivity; Protein Isoforms; Proteins; Proteomics; Research; Research Personnel; Risk; Risk Factors; Sampling; Scientist; Serum; Structural Protein; Structure; System; Technology; Time; Tissues; Training; Universities; Variant; Work; atherosclerosis risk; cardiovascular disorder risk; cardiovascular risk factor; career development; clinically relevant; cohort; coronary artery calcification; drug development; expectation; glucose metabolism; glycation; indexing; insight; interest; knowledge base; medical schools; new technology; novel; overexpression; particle; protein structure; recruit; reverse cholesterol transport; skills; symposium; tissue culture; tool

Project Summary/Abstract High-density lipoprotein cholesterol (HDL-C) concentration is inversely associated with atherosclerotic cardiovascular disease (ASCVD) risk. However, recent data suggest that a measure of HDL particle function, HDL efflux capacity, may be a stronger predictor of ASCVD risk than HDL cholesterol level. HDL particles are composed of apolipoprotein A1 (apoA1) and enzymes embedded in a spherical phospholipid layer that surrounds a lipid core. One of the hypothesized protective functions of HDL particles is reverse cholesterol transport (RCT), which is the flux of cholesterol from peripheral tissues to the liver, where it is metabolized or excreted. HDL efflux capacity is the rate-limiting step of RCT. We hypothesize that variation in HDL efflux capacity is due to variation in apoA1 structure, which is a key mediator of this complex biochemical process. Top Down Proteomics is a novel technology, which allows for highly detailed characterization of apoA1 structural variants (proteoforms). The scientific aims of this K23 proposal are to: 1) define the spectrum of apoA1 and apoC3 proteoforms that are present in a sample of cohort participants and Northwestern outpatients, 2) determine the biologic variability of apoA1 proteoform expression over time, and 3) quantify the associations among apoA1 proteoforms, traditional risk factors, high-density lipoprotein (HDL) efflux capacity, and subclinical atherosclerosis. I am a practicing cardiologist and epidemiologist with interest in life course patters in cardiovascular disease and lipid-associated atherosclerotic cardiovascular risk. I currently hold a dual appointment in the Division of Cardiology and the Department of Preventive Medicine at Northwestern University Feinberg School of Medicine. Although I have training and expertise in long-term risk estimation and methods to describe patterns in cardiovascular risk across the life course, I aim to develop expertise in a molecular epidemiologic approach to quantifying lipid-associated atherosclerotic risk. To achieve the translational aims of this proposal I have assembled a mentorship and advisory committee of world leaders in in clinical lipidology, cardiovascular risk estimation, HDL biology and function, Top Down Proteomics, and biometric analytic approaches to proteomic data. As I work to achieve the scientific aims of this proposal, I will spend a total of 6 months completing informal tutorials in proteomics and HDL laboratories, attend multiple lipid-focused conferences, and complete coursework in bioinformatics. I have a formal system of evaluation arranged with all of my advisors and clear expectations for productivity and personal development have been established. Upon completion of this career development award I will be able to transition to become an independent molecular epidemiologist with a focus on lipid-associated atherosclerotic risk. I am confident that I can achieve the scientific and career development aims of this proposal and become an independent researcher leading collaborative research efforts between top-down proteomics researchers, lipid-focused basic scientists, epidemiologists, and clinical researchers to ultimately reduce the incidence of ASCVD.

项目摘要/摘要 高密度脂蛋白胆固醇（HDL-C）浓度与动脉粥样硬化成反比 心血管疾病（ASCVD）风险。但是，最近的数据表明，HDL粒子函数的度量， 与HDL胆固醇水平相比，HDL外排能力可能是ASCVD风险的更强预测指标。 HDL颗粒是 由载脂蛋白A1（APOA1）和嵌入在球形磷脂层中的酶组成，该酶是 包围脂质核心。 HDL颗粒的假设保护功能之一是反向胆固醇 转运（RCT），这是从周围组织到肝脏的胆固醇的通量，在肝脏中被代谢或 排泄。 HDL外排能力是RCT的限速步骤。我们假设HDL外排的变化 容量是由于APOA1结构的变化，这是这种复杂的生化过程的关键介体。 自上而下的蛋白质组学是一项新型技术，可以对ApoA1进行高度详细的特征 结构变体（蛋白基）。该K23提案的科学目的是：1）定义 同类参与者和西北的样本中存在的APOA1和APOC3蛋白基础 门诊病人，2）确定apoA1蛋白相表达的生物学变异性，以及3）量化 APOA1蛋白质成型，传统危险因素，高密度脂蛋白（HDL）外排能力之间的关联， 和亚临床动脉粥样硬化。我是一名对生活课程感兴趣的心脏病专家和流行病学家 心血管疾病和脂质相关的动脉粥样硬化心血管风险的模式。我目前持有 西北地区心脏病学和预防医学系的双重任命 大学费恩伯格医学院。尽管我有长期风险估计的培训和专业知识 以及描述整个生活过程中心血管风险模式的方法，我旨在发展专业知识 分子流行病学方法来量化脂质相关的动脉粥样硬化风险。实现 该提议的翻译目的我召集了一个世界领导人的指导和咨询委员会 在临床脂质学，心血管风险估计，HDL生物学和功能，自上而下的蛋白质组学和 蛋白质组学数据的生物特征分析方法。当我努力实现该提议的科学目标时，我将 总共花6个月完成蛋白质组学和HDL实验室的非正式教程，参加多个 以脂质为中心的会议，并完成生物信息学的课程。我有正式的评估系统 与我所有的顾问一起安排，对生产力和个人发展的明确期望 已确立的。完成此职业发展奖后，我将能够过渡成为 独立的分子流行病学家专注于脂质相关的动脉粥样硬化风险。我有信心 我可以实现该提案的科学和职业发展目标，并成为独立的 研究人员领先的合作研究工作，自上而下的蛋白质组学研究人员，以脂质为中心 基础科学家，流行病学家和临床研究人员最终降低ASCVD的发生率。