Role of LSD1 in Hypertension and Renal Injury in Blacks

项目总结/摘要 这项翻译研究计划的重点是赖氨酸特异性脱甲基酶1（LSD 1），一种表观遗传调节因子 基因转录。该项目的总体目标是表明LSD 1（rs 587168）的多态性与 在血压调节和肾脏损伤的病理生理学中的作用，以及过量的盐皮质激素 受体活性介导这些作用。申请人将使用数据库方法解决此假设 (Aim 1）和黑人高血压患者的生理学导向研究（目的2）。具体目标1将决定是否 黑人LSD 1风险等位基因携带者比非风险等位基因携带者有更大的肾损害（蛋白尿）证据。 申请人将在180名高血压黑人（90名风险和90名非风险LSD 1）中进行横断面研究 等位基因携带者）从国际高血压病型队列（HyperPATH）评估尿 白蛋白/肌酸酐水平（肾小球和肾小管损伤的标志物）和肾损伤分子-1（标志物 肾小管损伤）在黑人LSD 1风险等位基因携带者中高于非风险等位基因携带者。具体目标2 是一项在高血压黑人LSD 1风险等位基因携带者中进行的原理验证生理学研究， 通过基因驱动的抗高血压方法， （盐皮质激素受体拮抗剂，依普利酮）相比，非特异性的方法（ESTA）。56 受试者将参加一项为期12周的随机、双盲、活性对照、门诊研究，以评估 依普利酮（LSD 1特异性治疗）是否证明在24小时动态收缩压方面具有上级优势 非特异性治疗（non-specific treatment）如果Aim 1为阳性，申请人还将评估 尿白蛋白和KIM-1水平的纵向研究。成功完成这些目标将记录 遗传标记LSD 1是否可以识别出血压对血压有独特反应的黑人个体， 盐皮质激素受体阻滞剂--个性化精准医疗。此外，该项目的成果 有可能减少继发于血压控制不良的健康结果的黑人-白人差异。 培训计划包括由Gordon威廉姆斯，医学博士（导师）和盖尔阿德勒，医学博士，博士（合作）专门指导。 Mentor），心血管内分泌领域的国际专家。除了威廉姆斯和阿德勒博士 申请人将有一个咨询团队，由伯纳德罗斯纳博士（统计学家），约瑟夫邦文特， 医学博士，博士（肾脏病学家）和赫尔曼泰勒，医学博士（心脏病学家），每个提供专门知识，为申请人的 需求和目标。此外，申请人将完成临床/翻译研究、临床 试验设计和统计数据在哈佛T. H.公共卫生学院。这些活动将提供 申请人拥有必要的工具，这些工具对她成为一名独立患者的目标至关重要， 心血管内分泌学领域的研究者。

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.