CFTR REGULATION OF ION CHANNELS

在囊性纤维化（CF）患者中有缺陷的基因编码 一种被称为囊性纤维化跨膜传导调节因子的蛋白质 （CFTR）。CFTR是跨膜蛋白超家族的成员 称为ATP结合盒（ABC）转运蛋白。很明显 CFTR作为cAMP依赖性蛋白激酶A刺激的氯离子发挥功能 (CI-)频道尽管CI通道活动异常， cAMP依赖性蛋白激酶A（PKA）刺激CI分泌， 这是CF影响的上皮细胞的主要特征， 是功能失调的CFTR蛋白的直接结果，有一些 其他离子转运异常是CF的特征， 受影响的上皮细胞越来越多的证据表明，CFTR可以 与其他通道蛋白相互作用，并作为通道调节剂， 做一些ABC运输机。我们的假设是CFTR是一个 作为离子通道调节剂的双功能肽， 转运蛋白以及受调节的CI通道。更是 可能作为通道调节器的能力取决于域 ABC转运蛋白超家族的许多成员所共有的。的 本申请中提出的研究将研究CFTR如何作为 通道调节器将使用电压钳和膜片钳技术 剖析控制CFTR与离子相互作用的机制， 渠道，并确定哪些领域的CFTR参与这些 交互.这个项目的最终目标是应用洞察力 从这些CFTR功能的基础科学研究中获得的， 囊性纤维化患者的临床管理。

The gene that is defective in patients with cystic fibrosis (CF) encodes a protein termed the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a member of a superfamily of transmembrane proteins known as the ATP Binding Cassette (ABC) Transporters. It is clear that CFTR functions as a cAMP dependent protein kinase A stimulated chloride (CI-) channel. Although abnormal CI- channel activity, specifically cAMP- dependent protein kinase A (PKA) stimulation of CI- secretion, is a predominant feature of CF- affected epithelial cells and believed to be a direct result of the dysfunctional CFTR protein, there are a number of other ion transport abnormalities that are characteristic of CF- affected epithelial cells. There is increasing evidence that CFTR can interact with other channel proteins and act as a channel regulator as do a number of the ABC transporters. Our hypothesis is the CFTR is a bifunctional peptide that acts as a regulator of ion channels and transporters as well as a regulated CI- channel. Furthermore it is likely that the ability to act as a channel regulator depends on domains that are common to many members of the ABC transporter superfamily. The studies proposed in this application will examine how CFTR acts as a channel regulator. Voltage clamp and patch clamp techniques will be used to dissect the mechanisms that control CFTR's interactions with ion channels and identify which domains of CFTR participate in these interactions. The ultimate goal of this project is to apply insights gained from these basic science studies of CFTR function to improve the clinical management of cystic fibrosis patients.