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

项目总结/摘要 高密度脂蛋白胆固醇（HDL-C）浓度与动脉粥样硬化呈负相关 心血管疾病（ASCVD）风险。然而，最近的数据表明，HDL颗粒功能的测量， HDL外排能力可能是比HDL胆固醇水平更强的ASCVD风险预测因子。HDL颗粒 由载脂蛋白A1（apoA 1）和包埋在球形磷脂层中的酶组成， 围绕着脂质核心。高密度脂蛋白颗粒的一个假设的保护功能是逆转胆固醇 胆固醇转运（RCT），是胆固醇从外周组织流向肝脏，在肝脏中代谢或 排泄HDL外排能力是RCT的限速步骤。我们假设HDL流出的变化 能力是由于apoA 1结构的变化，这是这个复杂的生化过程的关键介质。 自上而下的蛋白质组学是一种新的技术，它允许对apoA 1进行高度详细的表征 结构变体（蛋白质型）。这个K23建议的科学目的是：1）定义 apoA 1和apoC 3蛋白质型存在于队列参与者和西北大学的样本中， 门诊患者，2）确定apoA 1蛋白质表达随时间的生物学变异性，3）量化 载脂蛋白A1蛋白形式、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。我是一名执业心脏病学家和流行病学家，对生命历程感兴趣 心血管疾病模式和脂质相关动脉粥样硬化心血管风险。目前，我持有A 在西北大学心脏病科和预防医学系的双重任命 范伯格大学医学院。虽然我受过长期风险评估的训练 和方法来描述整个生命过程中的心血管风险模式，我的目标是发展专业知识， 量化脂质相关动脉粥样硬化风险的分子流行病学方法。实现 我已经召集了一个由世界领导人组成的指导和咨询委员会， 临床脂质学，心血管风险评估，HDL生物学和功能，自上而下的蛋白质组学， 蛋白质组学数据的生物测定分析方法。在我努力实现这项提案的科学目标时，我将 花了6个月的时间完成蛋白质组学和HDL实验室的非正式教程，参加多个 脂质为重点的会议，并在生物信息学完成课程。我有一个正式的评估系统 我与我所有的顾问都安排好了，对生产力和个人发展有着明确的期望， 确立了习在完成这个职业发展奖后，我将能够过渡到成为一名 独立分子流行病学家，专注于脂质相关动脉粥样硬化风险。我深信 我能达到这个建议的科学和职业发展目标，成为一个独立的 领导自上而下的蛋白质组学研究人员之间的合作研究工作的研究员，以脂质为重点， 基础科学家，流行病学家和临床研究人员，以最终降低ASCVD的发病率。

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.