AIRWAY EPITHELIAL CELL CHLORIDE CHANNELS

描述(直接从应用程序中获取) 我们研究的中心假设是CFTR介导的丢失， 根尖膜氯电导是最基本的生理缺陷。 这会导致囊性纤维化中的呼吸道疾病。我们的总目标是 研究就是要证实或否定这一假设。最令人费解的方面 慢性肺病就是这样开始的。对这个问题的直接攻击是 目前还不可能，因为还没有合适的人肺的动物模型 疾病是存在的。在其他地方，我们提出了一种战略来生产这样的模式。 在这里，我们提出了用现有的模型组织进行可行的实验。 这涉及到CF研究中的两个最基本的问题：如何 CFTR作为离子通道运行，以及其他氯离子通道是什么 肺脏中的重要角色。该提案有4个具体目标。目标1是 理解自然的作用机制和功能意义 我们在人CFTR通道中发现的“锁定-打开”动力学 呼吸道细胞。目标2是检验CFTR中某些突变的假设 全部或部分导致疾病，因为它们干扰CFTRs 能够显示锁定-打开动态。目标3是确定其他 氯通道，并确定它们在呼吸道细胞功能中的作用。目标4 是研究发生在上皮细胞上的通道群体的变化 极化。

DESCRIPTION (Taken directly from the application) The central hypothesis of our research is that the loss of CFTR-mediated, apical membrane chloride conductance is the fundamental physiological defect that leads to airways disease in cystic fibrosis. The general goal of our research is to confirm or negate that hypothesis. The most puzzling aspect of CF lung disease is how it begins. A direct attack on that question is not possible at present because no adequate animal model of human CF lung disease exists. Elsewhere, we propose a strategy to produce such a model. Here, we propose experiments that are feasible with available model tissues and that deal with two of most basic questions in CF research: how does CFTR operate as an ion channel, and what other chloride ion channels are important players in the lung. The proposal has 4 specific aims. Aim 1 is to understand the mechanism and functional significance of natural "lock-open" kinetics that we have discovered in CFTR channels of human airway cells. Aim 2 is to test the hypothesis that some mutations in CFTR lead to disease in whole or in part because they interfere with CFTR's ability to display locked-open kinetics. Aim 3 is to identify other chloride channels and determine their role in airway cell function. Aim 4 is to study changes in channel populations that occur with epithelial cell polarization.