Epigenetic Regulation of Kidney Function and Blood Pressure

肾功能和血压的表观遗传调控

• 批准号: 10579236
• 负责人: Zhongjie Sun
• 金额: $ 44.94万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579236
• 关键词: Address; Affect; Age; Aging; Attenuated; Blood Pressure; Cardiovascular Diseases; Cells; Data; Development; Disease; Distal convoluted renal tubule structure; Down-Regulation; Elderly; Embryonic Development; Environment; Epigenetic Process; Excretory function; Gene Delivery; Gene Expression; Genes; Genetic Transcription; High Prevalence; Histones; Hypertension; Impairment; Incidence; Kidney; Knock-out; Lysine; Maintenance; Methylation; Molecular; Mus; Mutation; Pathogenesis; Population; Positioning Attribute; Prevalence; Preventive; Regulation; Renal function; Research; Role; Sodium Chloride; Suppressor Genes; Testing; Therapeutic; Therapeutic Intervention; Time; Up-Regulation; Work; aged; aging population; attenuation; blood pressure regulation; effective intervention; epigenetic regulation; in vivo; innovation; insight; kidney dysfunction; knockout gene; novel; novel strategies; novel therapeutic intervention; preventive intervention; salt sensitive hypertension; symporter

Project Summary/Abstract It is well established that the incidence of hypertension increases with age. The prevalence of hypertension is higher in the aged (~62%) than in the young population (~11%). Salt sensitivity is more prevalent in the elderly population. The aging-related salt sensitivity is an important factor that contributes to the high prevalence of hypertension in the elderly population. Lysine (K)-specific demethylase 6a (KDM6A) is a recently-discovered powerful H3K27me3 demethylase. It is not known, however, if KDM6A is involved in the maintenance of blood pressure (BP). Whether KDM6A gene deficiency causes hypertension has never been determined. The objective of the proposed research is to determine whether KDM6A plays a role in the maintenance of BP and whether KDM6A gene deficiency is involved in the pathogenesis of hypertension. This objective will be achieved by pursuing two interrelated specific aims using a combination of several novel approaches including kidney- specific conditional gene knockout, epigenetic analysis, and in vivo kidney-specific gene delivery. The specific aims are: (1) Determine whether KDM6A plays a role in the regulation and maintenance of normal kidney function and blood pressure. (2) Determine whether in vivo expression of KDM6A attenuates aging-related impairment in renal Na excretion and hypertension. These studies will demonstrate, for the first time, an important role of KDM6A in the regulation of blood pressure and the pathogenesis of hypertension. The results will provide novel mechanism that KDM6A may protect the kidney. Completion of the project may reveal new insights into therapeutic strategies for hypertension and related cardiovascular disorder.

项目总结/摘要 众所周知，高血压的发病率随着年龄的增长而增加。之时尚 高血压在老年人中（约62%）高于年轻人（约11%）。盐敏感性是 在老年人群中更为普遍。与老化相关的盐敏感性是一个重要因素， 导致老年人高血压患病率高。赖氨酸（K）特异性 脱甲基酶6a（KDM 6A）是最近发现的一种高效的H3 K27 me 3脱甲基酶。不知道， 然而，如果KDM 6A参与维持血压（BP）。KDM 6A基因是否 缺乏导致高血压的原因从未被确定。拟议研究的目标 目的是确定KDM 6A是否在维持血压中起作用，以及KDM 6A基因是否与血压相关。 虚与高血压病的发病有关。这一目标将通过以下方式实现： 两个相互关联的具体目标，使用几种新方法的组合，包括肾脏- 特异性条件基因敲除、表观遗传分析和体内肾特异性基因递送。的 具体目标是：（1）确定KDM 6A是否在调节和维持 肾功能和血压正常(2)确定KDM 6A的体内表达是否 减轻肾钠排泄和高血压中与衰老相关的损害。这些研究将 首次证明了KDM 6A在调节血压和血压调节中的重要作用。 高血压的发病机制这一结果为KDM 6A保护细胞凋亡提供了新的机制。 肾该项目的完成可能会揭示高血压治疗策略的新见解 以及相关的心血管疾病。