Epigenetic Regulation of Kidney Function and Blood Pressure

肾功能和血压的表观遗传调节

• 批准号: 9765836
• 负责人: Zhongjie Sun
• 金额: $ 47.96万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765836
• 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; Molecular; Mus; Mutation; Pathogenesis; Play; Population; Positioning Attribute; Prevalence; Preventive; Preventive Intervention; 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; salt sensitive hypertension; targeted treatment

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.

项目概要/摘要 众所周知，高血压的发病率随着年龄的增长而增加。患病率 老年人（约 62%）的高血压发病率高于年轻人（约 11%）。盐敏感性为 在老年人群中更为普遍。与衰老相关的盐敏感性是一个重要因素 导致老年人群中高血压患病率较高。赖氨酸 (K) 特异性 去甲基酶 6a (KDM6A) 是最近发现的一种强大的 H3K27me3 去甲基酶。据了解， 然而，如果 KDM6A 参与维持血压 (BP)。是否有KDM6A基因 缺乏导致高血压的原因尚未确定。拟议研究的目标 目的是确定KDM6A是否在BP的维持中发挥作用以及KDM6A基因是否 缺乏参与高血压的发病机制。这一目标将通过追求实现 结合使用几种新方法（包括肾- 特定条件基因敲除、表观遗传分析和体内肾脏特异性基因传递。这 具体目标是：（1）确定KDM6A是否在调节和维持 肾功能和血压正常。 (2)确定KDM6A体内是否表达 减轻与衰老相关的肾钠排泄损伤和高血压。这些研究将 首次证明 KDM6A 在血压调节和血压调节中的重要作用 高血压的发病机制。该结果将为KDM6A保护细胞提供新的机制。 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。