Role of LSD1 in Hypertension and Renal Injury in Blacks

项目摘要/摘要 这项翻译研究计划的重点是赖氨酸特异的脱甲基酶1(LSD1)，一种表观遗传调节因子 基因转录的结果。该项目的总体目标是显示LSD1(Rs587168)中的多态 在黑人血压调节和肾脏损伤的病理生理学方面，以及过量的盐皮质激素 受体活性介导了这些效应。申请者将使用数据库方法解决这一假设 (目标1)和一项针对黑人高血压患者的生理学指导研究(目标2)。具体目标1将决定是否 黑人LSD1风险等位基因携带者比非风险等位基因携带者有更多的肾脏损害(蛋白尿)证据。 申请者将对180名高血压黑人(90名有风险的和90名无风险的LSD1)进行横断面研究 等位基因携带者)，以评估尿液是否 白蛋白/肌酐水平(肾小球和肾小管损伤的标志物)和肾脏损伤分子-1(标志物 在黑人LSD1风险等位基因携带者中比非风险等位基因携带者中更高。具体目标2 是一项在高血压黑人LSD1风险等位基因携带者中进行的验证性生理学研究，检验了以下假设 通过基因驱动的降压方法，血压的降幅将更大 (盐皮质激素受体拮抗剂依普利酮)与非特异性方法(氨氯地平)进行比较。56 参与者将参加为期12周的随机、双盲、主动对照、门诊研究，以评估 依普利酮(LSD1特异性治疗)是否优于24小时动态收缩压 降幅大于氨氯地平(非特异性治疗)。如果Aim1是肯定的，申请者还将评估 尿白蛋白和尿KIM-1水平的纵向研究。成功完成这些目标将记录 一种名为LSD1的遗传标记是否识别出血压对其有独特反应的黑人个体 盐皮质激素受体阻滞剂--个性化、精准药物。此外，该项目的成果具有 有可能减少因血压控制不佳而导致的健康结局中的黑白差异。 培训计划包括由医学博士戈登·威廉姆斯(Mentor)和医学博士盖尔·阿德勒(Gail Adler)(共同 Mentor)，心血管内分泌学领域的国际专家。除了威廉姆斯博士和阿德勒博士， 申请者将有一个顾问团队，由伯纳德·罗斯纳博士(统计学家)、约瑟夫·邦文特尔、 医学博士(肾病学家)和赫尔曼·泰勒医学博士(心脏病专家)，每个人都提供适合申请者的专业知识 需求和目标。此外，申请者还将完成临床/转化性研究、临床 哈佛大学公共卫生学院的试验设计和统计。这些活动将提供 申请者拥有必要的工具，对于实现成为独立患者的目标至关重要- 心血管内分泌学领域的定向研究员。

PROJECT SUMMARY/ABSTRACT This translational research proposal focuses on lysine-specific demethylase 1 (LSD1), an epigenetic regulator of gene transcription. The project’s overall aim is to show that polymorphisms in LSD1 (rs587168) are involved in blood pressure regulation and the pathophysiology of renal injury in Blacks, and that excess mineralocorticoid receptor activity mediates these effects. The applicant will address this hypothesis using a database approach (Aim 1) and a physiology-directed study in Black hypertensives (Aim 2). Specific Aim 1 will determine whether Black LSD1 risk allele carriers have greater evidence of renal damage (albuminuria) than non-risk allele carriers. The applicant will perform a cross-sectional study in 180 hypertensive Blacks (90 risk and 90 non-risk LSD1 allele carriers) from the International Hypertension Pathotype Cohort (HyperPATH) to assess whether urine albumin/creatinine levels (marker of renal glomerular and tubular damage) and Kidney Injury Molecule-1 (marker of renal tubular damage) are higher in Black LSD1 risk allele carriers vs non-risk allele carriers. Specific Aim 2 is a proof-of-principle physiologic study in hypertensive Black LSD1 risk allele carriers testing the hypothesis that reductions in blood pressure will be greater with a genetically-driven anti-hypertensive approach (mineralocorticoid receptor antagonist, eplerenone) compared to a non-specific approach (amlodipine). 56 participants will be enrolled in a 12-week randomized, double-blind, active controlled, outpatient study to assess whether eplerenone (LSD1 specific treatment) proves superior in 24-hr ambulatory systolic blood pressure reduction than amlodipine (non-specific treatment). If Aim1 is positive, the applicant will also assess change in urine albumin and KIM-1 levels in the longitudinal study. Successful completion of these Aims will document whether a genetic marker, LSD1, identifies Black individuals whose blood pressure is uniquely responsive to mineralocorticoid receptor blockade--personalized, precision medicine. Further, results of this project have the potential to reduce Black-White disparities in health outcomes secondary to poor blood pressure control. The training plan includes dedicated mentorship by Gordon Williams, MD (Mentor) and Gail Adler, MD, PhD (co- Mentor), international experts in the field of cardiovascular endocrinology. In addition to Drs. Williams and Adler, the applicant will have an advisory team composed of Bernard Rosner, PhD (statistician), Joseph Bonventre, MD, PhD (nephrologist), and Herman Taylor, MD (cardiologist), each offering expertise tailored to the applicant’s needs and goals. Also, the applicant will complete formal training in clinical/translational investigation, clinical trial design, and statistics at the Harvard T.H. Chan School of Public Health. These activities will provide the applicant with the necessary tools critical for development toward her goal of becoming an independent patient- oriented investigator in the field of cardiovascular endocrinology.