OBRIEN KIDNEY DISEASE CENTER

上皮Na通道分子本质的发现 （ENaC）已经迅速导致理解， 分子复合物，或负责其调节的因子， 对血压调节异常有很大的影响。 的 最有说服力的证据表明，异常的功能，他的通道 复杂的可以产生高血压来自患者 利德尔综合征，一种罕见的遗传性疾病， 激活其中一个通道亚基的突变。 这个奥布莱恩 中心计划将审查决定的重要因素， 这种分子复合物的结构和调节，以获得 了解其调节的异常如何有助于 NaCl敏感性高血压。 第一个项目将解决 集合管和尾水管ENaC对NA的调节作用 例外. 这些实验将测试新的假设， 内髓集合管中ENaC的过度活动 机械化到传入肾神经活动。 第二 该项目将侧重于ENaC的发展监管， 正常大鼠及盐敏感和耐盐大鼠模型 高血压 此外，使用一种不能 产生内源性糖皮质激素，实验将检查 糖皮质激素在ENaC中作用的特殊假说 发展过程中的表达。 第三个项目将侧重于 人ENaC γ亚基基因的调控。 的 初步数据表明，5 ′侧翼区含有 启动子活性和类固醇敏感性可能是由 非传统的反应机制。 本项目的信息 可以提供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 已知在Liddle综合征中引起ENaC过度活跃的人这样做 通过改变通道复合体在细胞中的插入和取回， 质膜 第五个项目将审查 在完整小鼠中过度表达和表达不足的ENaC的影响， 基因操控 这些实验将检验几个预测 来自细胞和器官系统的实验结果。 的 实验还将测试一些重要的假设， ENaC在高肾素高血压中的作用 单独的项目是 紧密交织在一起，产生一个跨学科的重点， 非常重要的分子复合物，当异常时， 能够产生重大的人类疾病。

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.