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: 9265497
• 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/9265497
• 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; Elements; Ensure; Enzymes; Epidemiology; Event; Exhibits; Female; General Population; Genetic Polymorphism; Genotype; Goals; 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; Program Development; Publications; Race; Reporting; Research; Research Personnel; Role; Sampling; 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; epidemiology study; ethnic diversity; improved; interest; laboratory experience; lipid disorder; lipid metabolism; macrophage; multidisciplinary; novel marker; nutrition; oxidation; population based; prospective; public health relevance; randomized trial; sex; skills; targeted treatment; therapeutic target; torcetrapib; translational scientist; vascular inflammation; 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; Elements; Ensure; Enzymes; Epidemiology; Event; Exhibits; Female; General Population; Genetic Polymorphism; Genotype; Goals; 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; Program Development; Publications; Race; Reporting; Research; Research Personnel; Role; Sampling; 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; epidemiology study; ethnic diversity; improved; interest; laboratory experience; lipid disorder; lipid metabolism; macrophage; multidisciplinary; novel marker; nutrition; oxidation; population based; prospective; public health relevance; randomized trial; sex; skills; targeted treatment; therapeutic target; torcetrapib; translational scientist; 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专注于应用基于实验室的技术，评估HDL功能的独立研究人员。迄今为止，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状动脉疾病风险预测，最终在几个第一任专家出版物中完成临床科学硕士学位。现在，我可以将此专业知识应用于我最感兴趣的HDL功能的生物标志物区域。我的直接研究目标是基于证据，表明直接评估人类研究中的HDL功能可能会导致更好地靶向旨在降低心血管疾病（CVD）风险的HDL修改疗法。这些集中的职业目标要求指导的职业发展途径，以获得必要的基于实验室的技能，以获得独立性，成为HDL代谢和CVD特定领域的转化临床研究者。我的职业发展计划的关键要素包括：1）多学科指导：菲利普·沙尔（Philip Shaul）博士是主要的转化科学家主要导师，而詹姆斯·德·莱莫斯（James de Lemos）博士是我现任人口科学研究的导师兼达拉斯心脏研究主任詹姆斯·德·莱莫斯（James de Lemos）博士； 2）实验室和临床研究课程； 3）直接实验室培训 HDL功能研究（UTSW的Philip Shaul； Dan Rader，Penn）；并准备R01赠款申请。该提案的目的是系统地研究一般人群中与CHD有关的两个主要HDL功能。我的中心假设是，HDL介导的巨噬细胞特异性胆固醇外排和eNOS的HDL激活（HDL功能）的血浆测量将根据种族，性别和代谢状态，并且与HDL-C与HDL-C的血管疾病无关。我计划通过前瞻性测量HDL功能在达拉斯心脏研究中收集的人血浆的现有生物库中前瞻性测量HDL功能（n = 2,971; 50％的非洲裔美国人； 50％女性）来追求以下三个特定目的：1）确定影响变异N HDL跨多种人群的生物学因素； 2）确定副氧酶-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。预计这些研究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，而不是简单的HDL-C浓度来降低CHD风险。 UT Southwestern结合了非凡的流行病学和转化研究机会和教师开发计划，这些计划将确保PI成功的临床研究职业，特别是由Scott Grundy博士领导的Helen Hobbs博士领导的达拉斯心脏研究，由Scott Grundy博士和临床科学系领导的营养中心，由临床科学系主持。