Genetic Epidemiology of Treatment Resistant Hypertension in African Americans

简介（由申请人提供）：菲利普斯博士是乔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发展独立的职业，以改善种族和少数民族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距的研究事业。他之前的研究主要集中在提高心脏衰竭疾病管理项目和健康差异方面的护理质量和临床结果。然而，在最近两年中，申请人将其研究重点扩大到心血管疾病二级预防的上游目标，包括高血压，这是一种常见的，重要的可改变的危险因素，是心肾功能障碍的前兆，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，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培训计划，旨在提供一个密集的，密切指导的，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、高级生物静力学和纵向数据管理、转化研究、临床试验设计和研究伦理方面的结构化教学课程。第三，培训环境和指导团队很好地配合，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相当多的专业知识。主要导师是莫尔豪斯医学院心血管研究所（CVRI）主任Gary H. Gibbons博士和亚特兰大临床与转化科学研究所（ACTSI）主任Arlene B. Chapman博士，后者在指导初级教师和博士后学员从事独立研究事业方面取得了成功和经验。最后，候选人还将设计、实施和完成一项临床研究项目，以开发试点数据，这将对未来在独立道路上成功申请资金至关重要。该候选人对非裔美国人治疗难治性高血压（定义为血压b> 140/90 mmHg，尽管bbbb3降压药达到最佳剂量，包括利尿剂）的自然史感兴趣。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裔美国人中很少。在奖励期间，候选人将设计并实施一项非裔美国人受试者的试点研究（N=247例与N=247例对照，血压<140/90mmHg和<2种药物），以测试一系列相关假设：i)与年龄/性别匹配的对照组相比，患有治疗抵抗性高血压的非裔美国人具有更高水平的促炎细胞因子、急慢性肾损伤生物标志物（微量白蛋白尿、蛋白尿和肾损伤标志物-1 [kim1]），以及血管僵硬度（脉搏波速度[PWV]和增强指数[Aix]）增加；ii)功能血管紧张素原（AGT）变异和AGT水平增加的等位基因频率显著更高；iii)在随访期间，促炎细胞因子水平、肾损伤生物标志物、AGT变异体改变全身和肾内RAAS激活对预测肾功能障碍有附加作用。

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.