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.

项目概要/摘要该转化研究计划重点关注赖氨酸特异性脱甲基酶 1 (LSD1)，一种表观遗传调节因子该项目的总体目标是证明 LSD1 (rs587168) 的多态性参与其中。黑人的血压调节和肾损伤的病理生理学，以及过量的盐皮质激素受体活性介导这些效应，申请人将使用数据库方法来解决该假设。（目标 1）和针对黑人高血压的生理学研究（目标 2）将确定是否。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损伤（白蛋白尿）证据。申请人将对 180 名高血压黑人（90 名有风险的 LSD 和 90 名无风险的 LSD1）进行横断面研究等位基因携带者）从国际高血压病理型队列（HyperPATH）中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）和肾损伤 Molecule-1（肾损伤分子 1）（肾损伤标志物）黑色 LSD1 风险等位基因携带者与非风险等位基因携带者相比，肾小管损伤）更高。是一项针对高血压黑人 LSD1 风险等位基因携带者的原理验证生理学研究，测试以下假设：通过基因驱动的抗高血压方法，血压的降低效果会更大（盐皮质激素受体拮抗剂，依普利农）与非特异性方法（氨氯地平）相比56。参与者将参加一项为期 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）在 24 小时动态收缩压方面是否表现出优越性比氨氯地平减少（非特异性治疗）如果 Aim1 为阳性，申请人还将评估变化。纵向研究中的尿白蛋白和 KIM-1 水平将记录成功完成这些目标。遗传标记 LSD1 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断——个性化、精准医疗此外，该项目的成果还有：减少因血压控制不良而造成的健康结果方面的黑人与白人差异的潜力。培训计划包括戈登·威廉姆斯医学博士（导师）和盖尔·阿德勒医学博士、博士（共同）的专门指导。导师），心血管内分泌学领域的国际专家。申请人将拥有一个由 Bernard Rosner 博士（统计学家）、Joseph Bonventre 组成的顾问团队， MD、PhD（肾脏病专家）和 Herman Taylor 医学博士（心脏病专家），各自提供针对申请人的情况量身定制的专业知识此外，申请人还将完成临床/转化研究、临床方面的正式培训。哈佛大学陈曾熙公共卫生学院的试验设计和统计数据将提供这些活动。申请人拥有对实现成为独立患者的目标至关重要的必要工具 - 心血管内分泌学领域的定向研究者。