Moving Beyond HDL Cholesterol, HDL Function as a Coronary Disease Biomarker

描述(由申请人提供)：我的职业目标是成为一名独立的调查员，专注于将基于实验室的技术应用于评估人类高密度脂蛋白功能的大量人群。到目前为止，我一直专注于获取临床研究技能，使我能够在达拉斯心脏研究中对新的生物标记物进行广泛的流行病学评估，以改善对冠状动脉疾病风险的预测，最终发表了几篇第一作者论文，并完成了临床科学硕士学位。我现在可以将这些专业知识应用于我最感兴趣的生物标记物领域--高密度脂蛋白功能。我的直接研究目标是基于证据，即直接评估人类研究中的高密度脂蛋白功能可能会导致更好地针对旨在降低心血管疾病(CVD)风险的高密度脂蛋白修饰疗法。这些专注的职业目标要求有指导的职业发展道路，以获得必要的基于实验室的技能集，以获得作为高密度脂蛋白代谢和心血管疾病特定领域的翻译临床医生研究员的独立性。我职业发展计划的主要内容包括：1)多学科指导：菲利普·绍尔博士作为主要导师，一位公认的翻译科学家，詹姆斯·德莱莫斯博士作为共同导师，他是我目前在人口科学研究方面的导师，也是达拉斯心脏研究生物标记物核心的主任；2)实验室和临床研究的课程工作；3)直接的实验室培训 高密度脂蛋白功能研究(菲利普·绍尔，UTSW；丹·雷德，宾夕法尼亚)；以及R01拨款申请的准备工作。这项建议的目的是在普通人群中系统地研究与CHD有关的两个主要的高密度脂蛋白功能。我的中心假设是，血浆中测量的高密度脂蛋白介导的巨噬细胞特异性胆固醇外流和高密度脂蛋白激活eNOS(高密度脂蛋白功能)将因种族、性别和代谢状态而显著不同，并与独立于高密度脂蛋白-C的血管疾病呈负相关。我计划通过前瞻性地测量从达拉斯心脏研究收集的广泛表型的现有人血浆生物库(n=2,971；50%非裔美国人；50%女性)中的高密度脂蛋白功能来检验这一假设，以追求以下三个特定目标：1)确定影响不同人群高密度脂蛋白功能差异的生物因素；2)确定对氧磷酶-1(PON-1)活性和基因型与高密度脂蛋白功能的关联；3)全面研究高密度脂蛋白功能在预测冠心病中的作用。这些研究有望产生重要的积极影响，因为对高密度脂蛋白功能的心血管流行病学的全面评估将迅速促进针对功能高密度脂蛋白途径的临床研究，而不是简单地浓缩高密度脂蛋白以降低冠心病风险。德克萨斯大学西南分校结合了非凡的流行病学和翻译研究机会以及教师发展计划，将确保PI的临床研究生涯取得成功，特别是由Helen Hobbs博士领导的达拉斯心脏研究、Scott Grundy博士领导的营养中心和Milton Packer博士领导的临床科学系。

DESCRIPTION (provided by applicant): My career goal is to become an independent investigator focused on applying laboratory-based techniques assessing HDL functions to large human populations. I have focused thus far on acquiring clinical research skills allowing me to pursue broad epidemiologic assessments of novel biomarkers in improving coronary disease risk prediction in the Dallas Heart Study, culminating in several first-author publications and completion of a Master's Degree in Clinical Sciences. I am now positioned to apply this expertise to the biomarker area that I am most interested in-HDL function. My immediate research goals are based on evidence that directly assessing HDL functions in human studies may lead to better targeting of HDL-modifying therapies aimed at reducing cardiovascular disease (CVD) risk. These focused career goals mandate a mentored career development pathway to acquire the necessary laboratory-based skill sets to gain independence as a translational clinician investigator in the specific field of HDL metabolism and CVD. Key elements of my career development plan include: 1) multi-disciplinary mentorship: Dr. Philip Shaul as primary mentor, an established translational scientist, and Dr. James de Lemos as co-mentor, my current mentor in population science research and director of the Dallas Heart Study biomarker core; 2) coursework in laboratory and clinical research; 3) direct laboratory training in HDL function studies (Philip Shaul, UTSW; Dan Rader, Penn); and preparation for R01 grant application. The objective of this proposal is to systematically investigate two major HDL functions in relation to CHD in the general population. My central hypothesis is that plasma measurements of HDL-mediated macrophage-specific cholesterol efflux and HDL activation of eNOS (HDL functions) will vary significantly according to race, sex, and metabolic status and inversely correlate with vascular disease independent of HDL-C. I plan to test this hypothesis by prospectively measuring HDL function in an extensively phenotyped existing biobank of human plasma collected from the Dallas Heart Study (n=2,971; 50% African American; 50% women) to pursue the following three specific aims: 1) identify the biological factors influencing variation n HDL functions across a diverse population; 2) determine the associations of paraoxonase-1 (PON-1) activity and genotype with HDL functions; 3) comprehensively investigate the role of HDL functions in predicting CHD. These studies are anticipated to have an important positive impact, because the comprehensive assessment of the cardiovascular epidemiology of HDL function will rapidly facilitate clinical investigations targeting functional HDL pathways rather than simple concentration of HDL-C to reduce CHD risk. UT Southwestern combines extraordinary epidemiologic and translational research opportunities and faculty development programs that will ensure the PI's successful clinical research career, specifically the Dallas Heart Study led by Dr. Helen Hobbs, the Center for Nutrition led by Dr. Scott Grundy, and the Department of Clinical Sciences led by Dr. Milton Packer.