Role of Regulated CIC CI Channels in CI Secretion in CF

超出所提供的空间。囊性纤维化跨膜调节剂（CFTR）是一个CI通道。在囊性纤维化（CF）中，由于CFTR被错误运输，或具有不同的成熟度、稳定性或单位电导，CI转运减少。其他离子通道的功能调节在CF中也异常，气道细胞炎症和细菌感染增加。这项建议的长期目标是通过激活另一种氯离子通道CIC2来降低囊性纤维化的严重程度。在与CFTR相同的气道上皮中发现了CIC2 CI通道，并且已经确定了在体内起作用的CIC2激活剂。CIC2 mRNA在CF中未被显示上调。然而，在合作研究中，使用基因组方法发现Kir4.2 K通道mRNA在几种CF小鼠模型的肺中上调。克隆和表达的通道是pka激活的。这个K通道可能通过残留的F508CFTR和包括CIC2在内的其他CI通道促进CI转运。本提案中需要解决的关键问题是，通过激活CIC2直接（或间接通过激活K通道）激活CI转运是否足以弥补CF中观察到的其他功能的损失。具体目标是：1)通过药理学和分子生物学方法确定CIC2功能是否可以与CFTR功能分离；2)利用药理学和分子生物学方法，明确CIC2在类似气道微环境条件下培养的气道细胞模型中的作用。3)定义激活CIC2对CI转运缺陷的纠正是否会影响其他cf相关的功能变化。将研究钠转运（ENaC）功能、钙活化CI通道（CLCA2）功能、炎症标志物和细菌易感性；4)明确Kir4.2 K通道的上调和激活在CF中的作用。这也将从CI转运、Na转运、CLCA2功能、炎症和细菌易感性等方面进行研究。性能StTE (S)(组织、城市、国家)的分子和细胞生理学辛辛那提大学医学院的电脑盒子670576辛辛那提,哦,45267 - 0576年的关键人员 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. The cystic fibrosis transmembrane regulator (CFTR) is a CI channel. In cystic fibrosis (CF), CI transport is reduced because the CFTR is mis-trafficked, or has different maturation, stability or unit conductance. Regulation of the function of other ion channels is also aberrant in CF, and airway cells have increased inflammation and bacterial infection. The long-term goal of this proposal is to reduce the severity of cystic fibrosis by activation of another chloride channel, CIC2. CIC2 CI channels are found in the same airway epithelia as CFTR, and activators of CIC2 that function in vivo have been identified. CIC2 mRNA has not been shown to be up-regulated in CF. However in collaborative studies, the mRNA for the Kir4.2 K channel was found to be up- regulated in the lung of several murine models of CF using genomic approaches. The cloned and expressed channel is PKA-activated. This K channel may help promote CI transport by residual F508CFTR and other CI channels including CIC2. The key questions to be addressed in this proposal are whether activation of CI transport by activation of CIC2 directly (or indirectly through activation of this K channel) will be sufficient to compensate for loss of other functions observed in CF. The Specific Aims are to: 1) Establish whether CIC2 function can be separated from CFTR function by using pharmacological and molecular biological approaches; 2) Define the role of CIC2 in airway cell models cultured in conditions similar to the airway microenvironment by using pharmacological and molecular biological approaches. 3) Define whether correction of the CI transport defect by CIC2 activation affects other CF-related changes in function. Na transport (ENaC) function, Ca-activated CI channel (CLCA2) function, and markers of inflammation and bacterial susceptibility will be studied; and 4) Define the role of up-regulation and activation of Kir4.2 K channel in CF. This will also be studied in terms of CI transport, Na transport, CLCA2 function, inflammation and bacterial susceptibility. PERFORMANCE StTE(S) (organization, city, state) Department of Molecular & Cellular Physiology University of Cincinnati College of Medicine PC Box 670576 Cincinnati, OH 45267-0576 KEY PERSONNEL ========================================Section End===========================================