CFTR REGULATION OF ION CHANNELS

囊性纤维化(CF)患者的缺陷基因编码 囊性纤维化跨膜电导调节蛋白 (CFTR)。Cftr是跨膜蛋白超家族的一员。 称为三磷酸腺苷结合盒(ABC)转运体。很明显， Cftr作为cAMP依赖的蛋白激酶A刺激的氯离子发挥作用 (CI-)频道。尽管不正常的CI通道活动，特别是 CAMP依赖的蛋白激酶A(PKA)对CI分泌的刺激 一种受CF影响的上皮细胞的主要特征，据信 是CFTR蛋白功能失调的直接结果，有一些 其他离子传输异常，这是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，作为通道调节器 做了一些ABC运输机。我们的假设是CFTR是一种 作为离子通道调节器的双功能肽和 转运体以及受监管的CI通道。此外，它是 充当通道调节器的能力可能取决于域 这对ABC运输机超级家族的许多成员来说都是常见的。这个 本申请中建议的研究将考察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CFTR域参与了这些渠道 互动。这个项目的最终目标是应用洞察力 从这些基础科学研究中获得CFTR功能，以提高 囊性纤维化患者的临床处理。

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.