Grant: Operating Grant

The respiratory disease Cystic Fibrosis results from mutations in a cell membrane protein, the cystic fibrosis transmembrane regulator (CFTR). The mutant CFTR protein is recognized by the endoplasmic reticulum quality control system (ERQC) and retained within the cell and proteolytically degraded. Thus Cystic Fibrosis is termed, a "protein trafficking disease". If the mutant CFTR can traffic correctly to the cell surface it is functional as a transporter of chloride ions. That is, if the ERQC can be subverted the mutant CFTR can traffic correctly to the cell surface where it can function and alleviate the symptoms of the disease. This application addresses the fundamental mechanism of the retention of mutant CFTR in the ER by the ERQC, and thus how the mechanism can be subverted. Cystic fibrosis is the most common fatal genetic disease in Canada. Although the gene and the most frequent allele were identified nearly 20 years ago by groups in Canada and the US, there is no therapy based on the alleviation of the basic defect. This project is designed to explore the mechanism of ERQC that we have identified targets that controls the recognition of mutant CFTR. There are a large number of "protein trafficking" diseases - including immune disorders, cystic fibrosis, emphysema and others, that arise from the retention of otherwise functional proteins in the ER by the ER quality control system. The goal of this project is to discover its mechanism and approaches to therapies.