ABNORMALITIES OF FLUID AND ELECTROLYTE TRANSPORT

尽管在了解遗传和分子基础方面取得了快速进展 可引起临床疾病。为了获得这样的知识，我们必须专注于 在呼吸道上皮细胞，因为这是目前最多的 重大疾病。在CF气道上皮细胞中，两种电解质的转运 缺陷已被描述：缺乏cAMP调节的c1-通透性 以及Na=吸收速率的增加。前者可以归因于 对磷酸化调节的c1-通道cftr功能障碍的研究 位于呼吸道上皮细胞的顶膜，但其作用机制 导致Na+吸收增加的原因尚不清楚。因为电解液 CF气道上皮细胞转运异常，已有研究认为 CF呼吸道液体的数量和成分将是 不正常。因此，许多调查人员认为 慢性阻塞性肺疾病的发病机制及病理生理研究 呼吸道积液。这一假设反过来又导致了 针对纠正假设的一些治疗方法的发展 呼吸道液体异常。不幸的是，首字母 假设尚未得到检验；这就是本提案的目标。这个 第一个目标是检验这样一种假设，即 CF上皮细胞产生的液体异常。我们将对此进行测试 通过测量流体的方向、速度和调节的假说 原代培养中粘膜液的运输和组成 正常和CF的呼吸道上皮细胞。我们还会问，一个品种 治疗手法会改变粘膜液。第二个目标是 验证CF气道对Na+吸收增加的假说 上皮细胞由于CFTR型阴离子通道的丧失。我们将测试 HCO3-通过根尖膜CFTR离开细胞的可能性 阴离子通道使细胞的顶端酸化。基于研究 在肾上皮细胞中，Ph的降低可能抑制Na+ 频道。在CF上皮细胞中，HCO3传导通路的丢失 顶膜可解除Na+通道的抑制作用。在配置文件中 上皮根尖膜中HCP3传导通路的缺失 可以解除对钠离子通道的抑制，从而增加净值 CF上皮细胞对Na+的吸收速率。这些研究应该提供 这些信息对于了解CF如何改变 因此可能会对突变是如何产生的提供新的见解 在cftr中引发疾病。

Despite rapid progress in understanding the genetic and molecular basis of CFTR cause clinical disease. To obtain such knowledge we must focus on airway epithelia, because that is currently the site of the most significant disease. In CF airway epithelia, two electrolyte transport defects have been described: a lack of CAMP-regulated C1- permeability and an increased rate of Na= absorption. The former can be attributed to dysfunction of CFTR -- a phosphorylation -regulated C1- channel located in the apical membrane of airway epithelia -- but the mechanisms that generate increased Na+ absorption are unknown. Because electrolyte transport is abnormal in CF airway epithelia, it has been assumed that the quantity and composition of CF respiratory tract fluid will be abnormal. Consequently, many investigators have supposed that the pathogenesis and pathophysiology of CF lung disease results from abnormal respiratory tract fluid. That assumption, in turn, has lead to the development of a number of therapies directed at correcting assumed abnormalities of respiratory tract fluid. Unfortunately, the initial assumption has not been tested; that is the goal of this proposal. The first aim is to test the hypothesis that the quantity and composition of fluid generated by CF epithelia is abnormal. We will test this hypothesis by measuring the direction, rate, and regulation of fluid transport a nd the composition of the mucosal fluid in primary cultures of normal and CF airway epithelia. We will also ask whether a variety of therapeutic maneuvers alter the mucosal fluid. The second aim is to test the hypothesis that Na+ absorption is increased in CF airway epithelium as a result of the loss of CFTR anion channels. We will test the possibility that HCO3- leaving the cell through apical membrane CFTR anion channels acidifies the apical region of the cell. Based on studies in renal epithelia it is possible that a reduction in Ph inhibits Na+ channels. In CF epithelia the loss of a HCO3- conduction pathway in the apical membrane could remove the inhibition of Na+ channels. In CF epithelia the loss of a HCP3- conduction pathway in the apical membrane could remove the inhibition of Na+ channels, thereby increasing the net rate of Na+ absorption in CF epithelia. These studies should provide information that is central to understanding how CF alters the respiratory tract fluid and thus may give new insights into how mutations in CFTR cause disease.