CYSTIC FIBROSIS MUTANT

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 囊性纤维化是当今美国最常见的致命遗传性疾病。长 本研究的长期目标是阐明囊性纤维化中潜在的分子缺陷 并设计治疗策略来纠正它们。囊性纤维化是由 囊性纤维化跨膜传导调节因子（CFTR），最常见的是通过 缺失编码Phe 508（dF 508）的三个核苷酸。Phe 508的缺失破坏了折叠 内质网中CFTR的途径。合成了dF 508 CFTR， 插入到ER的膜中，但它未能达到天然状态并积累 处于动力学捕获但可折叠的构象。值得注意的是，dF 508 CFTR 仍然可以作为氯离子通道，但由于质量控制，它不能被运输到 顶端质膜。在这个项目中，我们假设，通过利用伴侣蛋白， 我们可以改善dF 508 CFTR折叠，从而改善囊性变的临床表现， 纤维化我们想用cryoEM和其他生化证据来说明 缺陷CFTR调节物与哺乳动物伴侣蛋白的结合。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cystic fibrosis is the most common fatal genetic disease in the United States today. The long term goal of this research is to elucidate the underlying molecular defects in cystic fibrosis and design therapeutic strategies to correct them. Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), most commonly by deletion of three nucleotides encoding Phe508 (dF508). Loss of Phe508 disrupts the folding pathway of CFTR in the endoplasmic reticulum. dF508 CFTR is synthesized and properly inserted into the membrane of the ER but it fails to reach the native state and accumulates in a kinetically trapped, but foldable, conformation. It is important to note that dF508 CFTR can still function as a chloride channel but due to quality control, it fails to be transported to the apical plasma membrane. In this project, we hypothesize that, by utilizing a chaperonin, we can improve dF508 CFTR folding and thus ameliorate the clinical manifestations of cystic fibrosis. We would like to use cryoEM to accompany other biochemical evidence to illustrate the binding of the defective CFTR regulator with the mammalian chaperonin.