INTERACTION OF CFTR AND ORCC

囊性纤维化(CF)与多种功能障碍模式有关 呼吸道除了异常的氯-分泌，这是一个标志 这种疾病。这些其他异常包括增强的Na+ 蛋白质和蛋白质的重吸收、异常加工和贩运 膜泡和慢性假单胞菌感染。关键问题 CFTR(囊性纤维化跨膜电导调节因子)是如何 与这些其他流程进行交互，以确保它们正常运行 正常情况下？这是一个重要的问题，因为慢性萎缩性胃炎的死亡率 粘性粘液分泌物引起的反复肺部感染 而不是直接来自有缺陷的氯离子通道功能。它也是众所周知的 CFTR调节外向整流氯通道(ORCC)，该通道具有 不同于CFTRCl-通道的生物物理特性。在此期间 在授权期内，CFTR与ORCC之间的监管互动将是 作为一种模式进行研究，以详细定义具体的机制 CFTR可影响多个呼吸道上皮细胞突起。在……里面 此外，cftr跨膜区的功能作用将 被探索以更好地了解突变在跨膜中的作用 CF.中的域将解决以下问题：1.什么是 外向整流氯离子通道与外向氯离子通道的耦合机制 呼吸道细胞中的CFTR？2.CFTR的哪些结构域是关键的 Cftr与外向整流氯之间的调控相互作用 频道？最后，3.哪些氨基酸定义了cftr的孔？ 从这笔赠款中产生的信息可能有助于我们制定战略 CF的一种药物疗法。

Cystic Fibrosis (CF) is associated with several dysfunctional modes in airways in addition to the abnormal Cl- secretion which is a hallmark of the disease. These other abnormalities include enhanced Na+ reabsorption, abnormal processing and trafficking of proteins and membrane vesicles, and chronic Pseudomonas infection. The key question is how does CFTR (cystic fibrosis transmembrane conductance regulator) interact with these other processes to ensure that they function normally? This is an important question, since mortality in CF occurs from repeated lung infection brought about by viscous mucus secretions and not directly from defective Cl- channel function. It is also known that CFTR regulates outwardly rectifying Cl- channels (ORCCs) which have biophysical properties distinct from CFTR Cl- channels. During this grant period, the regulatory interaction of CFTR with ORCCs will be studied as a model to define in detail the specific mechanisms whereby CFTR can affect more than one airway epithelial cell process. In addition, the functional role of the transmembrane domains of CFTR will be explored to understand better the role of mutations in transmembrane domains in CF. The following questions will be addressed: 1. What is the mechanism of coupling between outwardly rectifying Cl- channels and CFTR in airway cells? 2. What structural domains of CFTR are critical for the regulatory interaction between CFTR and outwardly rectifying Cl channels? and finally, 3. Which amino acids define the pore of CFTR? Information generated from this grant may help us develop strategies for a pharmacologic therapy for CF.