Genetic Epidemiology of Treatment Resistant Hypertension in African Americans

非裔美国人难治性高血压的遗传流行病学

• 批准号: 8335423
• 负责人: Christopher O'Brian Phillips
• 金额: $ 13.6万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335423
• 关键词: Accounting; Acute; African American; Age; Albumins; Algorithms; American Heart Association; Angiotensinogen; Angiotensins; Animal Model; Antihypertensive Agents; Award; Awareness; Biological Markers; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic; Chronic Kidney Failure; Clinical; Clinical Medicine; Clinical Research; Clinical Sciences; Clinical Trials Design; Commit; Consensus; Creatinine; Data; Development Plans; Diabetes Mellitus; Disease Management; Disease Progression; Diuretics; Dose; Enrollment; Environment; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Essential Hypertension; Exhibits; Faculty; Functional disorder; Funding; Future; Gene Expression; Gene Frequency; Genetic; Genetic Polymorphism; Glomerular Filtration Rate; Goals; Graft Rejection; Guidelines; Health Services Research; Heart failure; Hylobates Genus; Hypertension; Inflammatory; Injury; Institutes; Interleukin-6; Internist; Kidney; Kidney Transplantation; Measures; Mentors; Microalbuminuria; Minority Groups; Morehouse School of Medicine; Natural History; Organ; Outcome; Pathogenesis; Pharmaceutical Preparations; Phenotype; Physicians; Physiologic pulse; Physiological; Pilot Projects; Play; Population; Postdoctoral Fellow; Predisposition; Prevalence; Primary Prevention; Proteinuria; Proteomics; Public Health; Quality of Care; Records; Renal function; Renin; Renin-Angiotensin-Aldosterone System; Reporting; Research; Research Ethics; Research Institute; Research Methodology; Research Project Grants; Research Training; Resistance; Resources; Risk; Risk Factors; Role; Secondary Prevention; Series; Serum; Severities; Site; Stratification; Structure; System; TNF gene; Testing; Time; Training; Training Programs; Translational Research; Tubular formation; Urine; Variant; career; career development; clinical application; cohort; cytokine; data management; design; didactic education; disease diagnosis; ethnic minority population; experience; follow-up; gain of function; genetic association; genetic epidemiology; health disparity; high risk; hypertension control; improved; indexing; interest; modifiable risk; outcome forecast; patient oriented research; professor; prognostic; programs; research and development; response; sex; success

DESCRIPTION (provided by applicant): Dr. Phillips is an internist and Associate Professor of Clinical Medicine at Morehouse School of Medicine, Atlanta, GA. The candidate's long-term goal is to develop an independent career with expertise in the application of genetic epidemiology, translational research methods and health services research to improve primary prevention, risk stratification and management of cardiovascular disease among racial and ethnic minorities. Dr. Phillips' is committed to developing a research career in primary prevention of cardiovascular disease and health disparities. His previous research has been focused on improving quality of care and clinical outcomes with respect to heart failure disease management programs and health disparities. However, during the recent two years the applicant has expanded his research focus to more upstream targets for secondary prevention of cardiovascular disease including hypertension which is a common, important modifiable risk factor and an antecedent to cardio-renal dysfunction, particularly in African Americans. Therefore, this career development and clinical research training program will enable the applicant to acquire additional training in genetic epidemiology and translational research including clinical applications of gene- expression, proteomics and biomarker profiling to improve risk stratification and predict disease progression and/or response to therapy. First, the proposed career development plan incorporates a multi-disciplinary training program designed to provide an intense, closely mentored, patient-oriented research experience. Second, the candidate will also enroll in a structured curriculum of didactic coursework in genetic epidemiology, advanced biostatics and longitudinal data management, translational research, clinical trial design and research ethics. Third, the training environment and mentoring team are well aligned to provide both the necessary resources and considerable expertise in genetic epidemiology and translational research, hypertension and vascular dysfunction. The primary mentor is Dr. Gary H. Gibbons who is Director of the Cardiovascular Research Institute (CVRI) at Morehouse School of Medicine and a Co-mentor Dr. Arlene B. Chapman, Director of the Atlanta Clinical and Translational Science Institute (ACTSI) who have established track records of success and experience with mentoring junior faculty and post-doctoral trainees towards independent research careers. Finally, the candidate will also design, implement and complete a clinical research project in order to develop pilot data which will be important for the success of future funding applications on the path to independence. The candidate is interested in the natural history of treatment resistant hypertension (defined as BP>140/90 mmHg despite >3 antihypertensive agents at optimum dose including a diuretic) in African Americans. Hypertension experts suggest prevalence estimates in the range of 8% to 30%. However, epidemiologic studies pertaining to this important public health problem are sparse in African Americans. During the award period, the candidate will design and implement a pilot study of African American subjects (N=247 cases versus N=247 controls with BP <140/90mmHg and <2 drugs) to test a series of interrelated hypotheses: i) African Americans with treatment resistant hypertension have higher levels of pro-inflammatory cytokines), biomarkers of acute and chronic renal injury (microalbuminuria, proteinuria and kidney injury marker-1 [KIM-1]), and increased vascular stiffness (pulse wave velocity [PWV] and augmentation index [Aix]) compared with age/sex matched controls: ii) Allele frequencies for gain of function angiotensinogen (AGT) variants and AGT levels are significantly higher: iii) levels of pro-inflammatory cytokines, biomarker of renal injury, AGT variants modify systemic and intra-renal RAAS activation have additive effects on predicting renal dysfunction during follow-up.

描述（由申请人提供）：菲利普斯博士是佐治亚州亚特兰大市莫尔豪斯医学院的内科医生和临床医学副教授。候选人的长期目标是发展一个独立的职业生涯，在遗传流行病学，转化研究方法和卫生服务研究的应用方面具有专业知识，以改善种族和少数民族心血管疾病的一级预防，风险分层和管理。菲利普斯博士致力于发展心血管疾病和健康差异的一级预防研究事业。他以前的研究一直专注于提高护理质量和心力衰竭疾病管理计划和健康差异方面的临床结果。然而，在最近两年中，申请人已将其研究重点扩展到心血管疾病二级预防的更多上游靶点，包括高血压，高血压是一种常见的重要可改变的风险因素，也是心肾功能障碍的先兆，特别是在非洲裔美国人中。因此，该职业发展和临床研究培训计划将使申请人能够获得遗传流行病学和转化研究方面的额外培训，包括基因表达，蛋白质组学和生物标志物分析的临床应用，以改善风险分层并预测疾病进展和/或对治疗的反应。首先，拟议的职业发展计划包括一个多学科的培训计划，旨在提供一个激烈的，密切指导，以病人为导向的研究经验。其次，候选人还将参加遗传流行病学，高级生物统计学和纵向数据管理，转化研究，临床试验设计和研究伦理的教学课程的结构化课程。第三，培训环境和指导团队非常一致，可以提供遗传流行病学和转化研究、高血压和血管功能障碍方面的必要资源和大量专业知识。主要导师是加里H博士。吉本斯博士是莫尔豪斯医学院心血管研究所（CVRI）的主任，也是阿琳B博士的共同导师。查普曼，亚特兰大临床和转化科学研究所（ACTSI）的主任谁建立了成功的跟踪记录和经验，指导初级教师和博士后学员走向独立的研究生涯。最后，候选人还将设计，实施和完成一个临床研究项目，以开发试点数据，这对于未来独立道路上的资金申请成功至关重要。该候选人对非裔美国人治疗难治性高血压的自然史（定义为BP>140/90 mmHg，尽管在最佳剂量下有>3种降压药物，包括利尿剂）感兴趣。高血压专家建议患病率估计在8%到30%之间。然而，有关这一重要公共卫生问题的流行病学研究在非洲裔美国人中很少。在奖励期间，候选人将设计和实施非裔美国人科目的试点研究（N=247例病例与N=247例对照，BP <140/90 mmHg且<2种药物），以检验一系列相关假设：i）患有难治性高血压的非洲裔美国人具有较高水平的促炎细胞因子，急性和慢性肾损伤的生物标志物（微量白蛋白尿、蛋白尿和肾损伤标志物-1（KIM-1））和血管僵硬度增加（脉搏波速度[PWV]和增强指数[Aix]）：ii）功能获得血管紧张素原（AGT）变体和AGT水平的等位基因频率显著更高：iii）促炎性细胞因子、肾损伤的生物标志物、AGT变体改变全身和肾内RAAS活化的水平对预测随访期间的肾功能障碍具有累加效应。