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

基本信息

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
项目类别：
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

项目摘要

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拥有专业知识，以改善少数族裔心血管疾病的初级预防、风险分层和管理。菲利普斯博士致力于发展心血管疾病初级预防和健康差异方面的研究事业。他之前的研究重点是提高心力衰竭疾病管理计划和健康差异方面的护理质量和临床结果。然而，近两年来，申请人将其研究重点扩大到心血管疾病二级预防的更多上游目标，包括高血压，高血压是一种常见的、重要的可改变的危险因素，也是心肾功能障碍的先决条件，特别是在非裔美国人中。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含一个多学科培训计划，旨在提供密集、密切指导、以患者为导向的研究经验。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学方面的结构化教学课程。第三，培训环境和指导团队协调一致，可以在遗传流行病学和转化研究、高血压和血管功能障碍方面提供必要的资源和丰富的专业知识。主要导师是莫尔豪斯医学院心血管研究所 (CVRI) 所长 Gary H. Gibbons 博士，副导师是亚特兰大临床与转化科学研究所 (ACTSI) 所长 Arlene B. Chapman 博士他们在指导初级教师和博士后学员走向独立研究职业方面建立了成功记录和经验。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，这对于未来独立之路上资金申请的成功至关重要。该候选人对非裔美国人难治性高血压（定义为尽管使用了超过 3 种最佳剂量的抗高血压药物（包括利尿剂），但血压>140/90 mmHg）的自然史感兴趣。高血压专家建议患病率估计在 8% 至 30% 范围内。然而，在非裔美国人中，与这一重要公共卫生问题相关的流行病学研究很少。在颁奖期间，候选人将设计并实施一项针对非裔美国人受试者的试点研究（N=247 例病例与 N=247 例血压 <140/90mmHg 和 <2 种药物的对照），以测试一系列相互关联的假设：患有难治性高血压的美国人的促炎细胞因子、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]）水平较高，并且与年龄/性别匹配的对照相比，血管僵硬度（脉搏波速度 [PWV] 和增强指数 [Aix]）： ii) 血管紧张素原 (AGT) 功能获得变异的等位基因频率和 AGT 水平显着更高： iii) 促血管紧张素原水平炎症细胞因子、肾损伤的生物标志物、AGT 变异改变全身和肾内 RAAS 激活，对随访期间预测肾功能障碍具有附加作用。