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

超越 HDL 胆固醇，HDL 作为冠心病生物标志物

• 批准号: 9053514
• 负责人: Anand Kumar Rohatgi
• 金额: $ 15.57万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053514
• 关键词: African American; Antiatherogenic; Applications Grants; Area; Arylesterase; Atherosclerosis; Biological; Biological Factors; Biological Markers; Blood Platelets; Cardiovascular Diseases; Case-Control Studies; Cause of Death; Cholesterol; Clinical; Clinical Research; Clinical Sciences; Coronary heart disease; Development Plans; Disease; Elements; Ensure; Enzymes; Epidemiologic Studies; Epidemiology; Event; Exhibits; Female; General Population; Genetic Polymorphism; Genotype; Goals; Health; Heart; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Inflammation; Insulin Resistance; Intervention Trial; LDL Cholesterol Lipoproteins; Laboratories; Laboratory Research; Lead; Link; Lipids; Master' s Degree; Measurement; Measures; Mediating; Mentors; Mentorship; Metabolic; Metabolism; NOS3 gene; Nicotinic Acids; Obesity; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Plasma; Population; Population Heterogeneity; Population Sciences; Positioning Attribute; Preparation; Prevention; Publications; Race; Reporting; Research; Research Personnel; Role; Sampling; Scientist; Teacher Professional Development; Techniques; Testing; Tissues; Translational Research; Variant; Vascular Diseases; Woman; aryldialkylphosphatase; base; biobank; cardiovascular disorder epidemiology; cardiovascular disorder risk; career; career development; clinical investigation; clinically relevant; disorder risk; ethnic diversity; heart disease risk; improved; interest; laboratory experience; lipid metabolism; macrophage; novel marker; nutrition; oxidation; population based; programs; prospective; randomized trial; sex; skills; targeted treatment; therapeutic target; torcetrapib; vascular inflammation

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.

描述（由申请人提供）：我的职业目标是成为一名独立研究者，专注于应用基于实验室的技术评估大量人群的 HDL 功能。到目前为止，我一直专注于获得临床研究技能，使我能够对新型生物标志物进行广泛的流行病学评估，以改善达拉斯心脏研究中的冠心病风险预测，最终发表几篇第一作者出版物并完成临床科学硕士学位。我现在准备将这些专业知识应用到我最感兴趣的生物标志物领域——HDL 功能。我近期的研究目标基于这样的证据：在人体研究中直接评估 HDL 功能可能会导致更好地靶向 HDL 修饰疗法，从而降低心血管疾病 (CVD) 风险。这些重点职业目标要求有一个受指导的职业发展途径，以获得必要的基于实验室的技能，从而获得独立作为 HDL 代谢和 CVD 特定领域的转化临床医生研究者。我的职业发展计划的关键要素包括：1）多学科指导：Philip Shaul 博士为主要导师，一位知名的转化科学家；James de Lemos 博士为联合导师，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志物核心主任； 2）实验室和临床研究课程； 3）直接实验室培训 HDL 功能研究（Philip Shaul，UTSW；Dan Rader，宾夕法尼亚大学）；并准备 R01 拨款申请。本提案的目的是系统地研究普通人群中与 CHD 相关的两种主要 HDL 功能。我的中心假设是，HDL 介导的巨噬细胞特异性胆固醇流出和 HDL eNOS 激活（HDL 功能）的血浆测量值将根据种族、性别和代谢状态而显着变化，并且与独立于 HDL-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（n=2,971；50%非裔美国人；50%女性）收集的现有人类血浆生物库中的 HDL 功能来检验这一假设，以实现以下三个具体目标：1）确定影响不同人群 HDL 功能变化的生物学因素； 2) 确定对氧磷酶-1 (PON-1) 活性和基因型与 HDL 功能的关联； 3）全面研究HDL功能在预测CHD中的作用。这些研究预计将产生重要的积极影响，因为对 HDL 功能的心血管流行病学的全面评估将迅速促进针对功能性 HDL 途径的临床研究，而不是简单地浓缩 HDL-C 来降低 CHD 风险。 UT Southwestern 结合了非凡的流行病学和转化研究机会以及教师发展计划，将确保 PI 成功的临床研究生涯，特别是由 Helen Hobbs 博士领导的达拉斯心脏研究、由 Scott Grundy 博士领导的营养中心以及由 Milton Packer 博士领导的临床科学系。