CYSTIC FIBROSIS MUTANT

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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病。《长河》 这项研究的目的是阐明囊性纤维化的潜在分子缺陷。 并设计治疗策略来纠正它们。囊性纤维化由基因突变引起 囊性纤维化跨膜电导调节因子(CFTR)，最常见的是通过 编码Phe508(DF508)的三个核苷酸的缺失。失去Phe508打乱了折叠 CFTR在内质网中的途径。合成了DF508 CFTR，并正确地 插入到内质网的膜中，但它无法达到自然状态并积累 以一种动态受困但可折叠的构象。需要注意的是，DF508 CFTR 仍然可以作为氯离子通道，但由于质量控制，它无法运输到 顶端质膜。在这个项目中，我们假设，通过利用伴侣， 我们可以改善DF508 CFTR的折叠，从而改善囊性病变的临床表现 纤维化症。我们想用低温电子显微镜结合其他生化证据来说明 有缺陷的cftr调节子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.