NEW PARADIGMS OF CFTR REGULATION

CFTR 监管的新范式

• 批准号: 6193602
• 负责人: KEVIN L KIRK
• 金额: $ 30.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193602
• 关键词: chloride channels; cystic fibrosis; diarrhea; gastrointestinal epithelium; ion channel blocker; membrane activity; phosphorylation; protein kinase A; protein protein interaction; protein structure function; tissue /cell culture

DESCRIPTION (Adapted from the Applicant's Abstract): The CFTR chloride channel is implicated in two major human diseases: cystic fibrosis (low CFTR activity) and secretory diarrhea (excessive CFTR activity). The development of rational treatment strategies for either disease requires a better understanding of what activates or inactivates the CFTR channel. Although it is clear that CFTR is stimulated by PKA-mediate phosphorylation of the large regulatory domain (R domain) within this channel, the mechanisms that control CFTR gating are still obscure. Two new paradigms of CFTR regulation will be explored: 1) the stabilization of CFTR channel activity by an intramolecular interaction between the amino-terminal tail (N-tail) and the R domain and 2) the coupling of CFTR gating to the membrane traffic machinery by an intermolecular interaction between the CFTR N-tail and syntaxin 1A. These paradigms will be explored by pursuing three Specific Aims. First, the mechanism by which the N-tail stabilizes CFTR channel activity will be defined. Subaims include testing the hypothesis that the N-tail controls channel gating by modulating the phosphorylation of key residues within the R domain. Second, the structural basis of the interaction between the N-tail and R domain will be defined. The nature of the physical interaction between these domains will be characterized and the hypothesis that CFTR channel gating can be disrupted by peptides that block this interdomain interaction will be tested. Third, the hypothesis that CFTR channel gating is regulated by interactions between this ion channel will be tested and that components of the membrane traffic machinery coordinate the regulation of ion transport and protein traffic in epithelial cells. The results of the proposed study should provide new information regarding the mechanisms that control the activity of the CFTR chloride channel; information that may lead to more effective strategies for manipulating CFTR function in diseases that involve this ion channel.

描述（改编自申请人的摘要）：CFTR氯化物通道 与两个主要的人类疾病有关：囊性纤维化（CFTR活性低） 和分泌性腹泻（过度CFTR活性）。理性的发展 两种疾病的治疗策略都需要更好地了解什么 激活或灭活CFTR通道。虽然很明显CFTR是 由大调节域的PKA-介入磷酸化刺激（r 域）在此通道内，控制CFTR门控的机制仍然是 朦胧。将探讨两个新的CFTR法规范例：1） 通过分子内相互作用稳定CFTR通道活性 氨基末端尾巴（N-Tail）和R域和2）CFTR耦合 通过分子间相互作用向膜交通机械门控 在CFTR N-尾和语法1A之间。这些范例将由 追求三个具体目标。首先，n尾的机制 将定义稳定CFTR通道活动。 Subiaim包括测试 N-Tail通过调节来控制通道门控的假设 R结构域内关键残基的磷酸化。其次，结构 N-Tail和R域之间的相互作用的基础将定义。这 这些域之间的物理互动的性质将被表征 以及CFTR通道门控可能被肽破坏的假设 阻止此域间相互作用将进行测试。第三，假设 CFTR通道门控受此离子通道之间的相互作用调节 进行测试，并且膜交通机械的组件协调 调节上皮细胞中离子运输和蛋白质流量。这 拟议研究的结果应提供有关 控制CFTR氯化物通道活性的机制；信息 这可能会导致操纵CFTR功能的更有效的策略 涉及该离子通道的疾病。