CYSTIC FIBROSIS MUTANT

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

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.