Role of LSD1 in Hypertension and Renal Injury in Blacks

LSD1 在黑人高血压和肾损伤中的作用

基本信息

批准号：
10478286
负责人：
Andrea Haas
金额：
$ 19.26万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-09-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478286
关键词：
Address Advisory Committees Affect Albumins Albuminuria Alleles Amlodipine Antihypertensive Agents Basic Science Biological Assay Black Populations Black race Blood Pressure Calcium Channel Cardiovascular system Chronic Kidney Failure Clinical Clinical Data Clinical Trials Design Collection Creatinine Cross-Sectional Studies Data Databases Development Diet Disease Doctor of Philosophy Double-Blind Method Endocrinology Enrollment Epigenetic Process Essential Hypertension Exhibits Functional disorder Future Genes Genetic Markers Genetic Polymorphism Genetic Transcription Goals Heart Diseases High Prevalence Human Hypertension Individual Injury to Kidney International Investigation KDM1A gene Kidney Knowledge Lead Learning Longitudinal Studies Mediating Mentors Mentorship Methodology Mineralocorticoid Receptor Mus Outcome Outpatients Participant Pharmaceutical Preparations Physicians Physiological Physiology Population Prevalence Public Health Schools Randomized Regulator Genes Research Research Personnel Research Proposals Risk Role Running Sampling Secondary to Sodium Statistical Data Interpretation Stroke Techniques Testing Training Translational Research Tubular formation United States Urine Variant Visit Wild Type Mouse Work antagonist base black/white disparity blood pressure control blood pressure elevation blood pressure reduction blood pressure regulation cardiovascular effects career cohort comorbidity drug efficacy eplerenone health disparity hypertension control hypertensive hypertensives improved novel strategies patient oriented pre-clinical precision medicine primary outcome rat KIM-1 protein renal damage risk variant salt sensitive secondary outcome side effect statistics tool treatment program urinary western diet

项目摘要

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.

项目摘要/摘要这项翻译的研究建议着重于赖氨酸特异性脱甲基酶1（LSD1），一种表观遗传调节剂基因转录。该项目的总体目的是表明LSD1（RS587168）中的多态性涉及在血压调节和黑人肾脏损伤的病理生理学中，超过盐皮质激素受体活性介导了这些作用。申请人将使用数据库方法解决这一假设（AIM 1）和黑色高血压的生理学指导研究（AIM 2）。特定目标1将确定是否与非风险等位基因载体相比，黑色LSD1风险等位基因载体具有更大的肾脏损伤证据（蛋白尿）。申请人将对180个高血压黑人进行横断面研究（90个风险和90个非风险LSD1 等位基因载体）从国际高血压病原体队列（HyperPath）来评估尿液是否是否白蛋白/肌酐水平（肾肾小球和管状损伤的标记）和肾损伤分子1（标记物具体目标2 是一项高血压黑色LSD1风险等位基因携带者的原则生理学研究，该假设是通过一般驱动的抗高血压方法，血压的降低将更大（矿物皮质激素受体拮抗剂，eplerenone）与非特异性方法（氨氯地平）相比。 56 参与者将参加为期12周的随机，双盲，主动控制的门诊研究，以评估在24小时的卧床收缩压中，eplerenone（LSD1特定治疗）是否证明优越还原比氨氯地平（非特异性治疗）。如果AIM1是正面的，则申请人还将评估变更纵向研究中的尿白蛋白和KIM-1水平。这些目标的成功完成将记录遗传标志物LSD1是否确定了血压唯一反应的黑人矿物皮质激素受体封锁 - 个性化的精密药物。此外，该项目的结果具有减少血压控制不良的健康结果中黑白分布的潜力。培训计划包括戈登·威廉姆斯（Gordon Williams），医学博士（Mentor）和医学博士盖尔·阿德勒（Gail Adler）的敬业精神职位（共同）导师），心血管内分泌学领域的国际专家。除了Drs。威廉姆斯和阿德勒，申请人将拥有一个由伯纳德·罗斯纳（Bernard Rosner），博士（统计学家）的咨询团队医学博士，博士（肾脏科医生）和医学博士赫尔曼·泰勒（心脏病专家），每位提供专家量身定制的专家需求和目标。此外，申请人将完成临床/翻译调查的正式培训，临床试验设计和哈佛T.H.的统计数据陈公共卫生学院。这些活动将提供申请人拥有开发至关重要的工具，以成为成为独立患者的目标 - 心血管内分泌学领域的定向研究者。