OBRIEN KIDNEY DISEASE CENTER

上皮性钠通道分子本质的发现 (ENAC)迅速使人们认识到， 分子复合体，或在负责其调节的因素中， 对血压的异常调节有很大的作用。这个 最有说服力的证据表明经络功能异常 复合体可产生高血压的患者来自于 利德尔~S综合征，一种罕见的遗传性疾病，可导致 激活其中一个通道亚基的突变。这位奥布莱恩 CENTER计划将考察决定 该分子复合体的结构和调节，以获得 洞察其监管中的异常可能如何有助于 对NaCI敏感的高血压。第一个项目将讨论角色 ENaC在集合管和尿路上皮调节NA中的作用 例外情况。这些实验将检验新的假设，即 内髓集合管中ENaC的过度活动 肾传入神经活动的机械化。第二 该项目将重点关注ENaC在中国的发展规律 正常大鼠及盐敏感和耐盐大鼠模型 高血压。此外，使用鼠标模型不能 产生内源性糖皮质激素，实验将检验 糖皮质激素在ENaC中作用的具体假说 在发育过程中的表达。第三个项目将重点放在 人ENaCγ亚基基因的调控。这个 初步数据表明，5‘侧翼区域包含 启动子活性和类固醇敏感性可能由一种 非传统应对机制。来自该项目的信息 可以提供有关基因区域的关键信息 高血压人群中该亚单位的异常调节。 第四个项目将测试特定突变的假设 已知导致利德尔-S综合征患者脑钠素过度活动 通过改变通道复合体在 质膜。第五个项目将检查集成的 ENaC高表达和低表达对正常小鼠的影响 基因操纵。这些实验将检验几个预测 源自细胞和器官系统的实验结果。这个 实验还将测试一些重要的假设，关于 ENaC在高肾素性高血压中的作用单独的项目是 紧密交织在一起，产生跨学科的关注 极其重要的分子复合体，当异常时， 能够引发重大人类疾病的。

The discovery of the molecular nature of the epithelial Na channel (ENaC) has rapidly lead to the understanding that defects in this molecular complex, or in the factors responsible for its regulation, contribute strongly to abnormal regulation of blood pressure. the most convincing evidence that abnormal function of t his channel complex can produce hypertension comes from patients with Liddle~s Syndrome, a rare genetic disorder that produces an activating mutation in one of the channel subunits. This O~Brien Center Program will examine the important factors determining the structure and regulation of this molecular complex in order to gain insight into how abnormalities in its regulation might contribute to NaCI-sensitive hypertension. the first project will address the role of ENaC in the collecting duct and uropithelium in regulating NA exception. the experiments will test the novel hypotheses that overactivity of ENaC in the inner medullary collecting duct mechanosesation to afferent renal nerve activity. The second project will focus on the developmental regulation of ENaC in the normal rat and in rat models of salt-sensitive and -resistant hypertension. In addition, using a mouse model incapable of producing endogenous glucocorticoids, experiments will examine specific hypotheses on the role of glucocorticoid hormone on ENaC expression during development. the third project will focus on the regulation of the human ENaC gamma subunit gene. The preliminary data indicate that the 5' flanking region contains promoter activity and that steroid sensitivity might e conferred by a non-traditional response mechanism. Information from this project could provide critical information on regions of the gene leading to abnormal regulation of this subunit in hypertensive populations. The fourth project will test the hypothesis that specific mutations known to cause overactivity of ENaC in Liddle~s Syndrome do so by altering the insertion and retrieval of the channel complex in the plasma membrane. The fifth project will examine the integrated effects of over- and under-expressing ENaC in intact mice using genetic manipulation. The experiments will test several predictions derived from experimental results in cell and organ systems. The experiments will also test some important hypotheses regarding the role of ENaC in high renin hypertension. The separate projects are tightly interwoven to produce an interdisciplinary focus on a critically important molecular complex that, when abnormal, is capable of producing significant human disease.