Epigenetic Regulation of Kidney Function and Blood Pressure

项目摘要/摘要 众所周知，高血压的发病率随着年龄的增长而增加。疾病的流行 老年人高血压(~62%)高于青年人群(~11%)。盐敏度是 在老年人群中更为普遍。与衰老相关的盐敏性是一个重要因素 导致了老年人群中高血压的高患病率。赖氨酸(K)专一性 去甲基酶6a(KDM6A)是新近发现的一种功能强大的H3K27me3去甲基酶。目前还不清楚， 然而，如果KDM6A参与维持血压(BP)。KDM6A基因是否 缺乏导致高血压的原因从未被确定。拟议研究的目的 目的是确定KDM6A是否在BP的维持中起作用以及KDM6A基因是否 虚证与高血压的发病机制有关。这一目标将通过以下方式实现 两个相互关联的具体目标，使用包括肾脏在内的几种新方法的组合- 特定的条件性基因敲除、表观遗传学分析和体内肾脏特异性基因传递。这个 具体目标是：(1)确定KDM6A是否在调节和维护 肾功能和血压正常。(2)检测KDM6A是否在体内表达 减轻肾脏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KDM6A在调节血压和 高血压的发病机制。这一结果将为KDM6A的保护作用提供新的机制。 肾脏。该项目的完成可能会为高血压的治疗策略提供新的见解 以及相关的心血管疾病。

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.