29 Attempts of facilitated trafficking ΔF508-CFTR to the plasma membrane

Abstract

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the Cystic Fibrosis transmembrane conductance regulator protein (CFTR), a cAMPregulated chloride channel. One of the most common mutation of CFTR is the deletion of phenylalanine in 508 position (DF508-CFTR). This mutation induces small conformational change hence CFTR trafficking is no more effective due to its rapid degradation by means of chaperon machinery. In CF airways, abnormal epithelial ion transport mainly initiates mucus stasis resulting in infections. In this study we tried to (1) understand intracellular trafficking of CFTR and DF508-CFTR, (2) facilitate transport of DF508-CFTR by means of relieving it from degradation and (3) create assay for the robotized high-throughput drugs screening. Using broad spectrum of methods from recombinant DNA and immunocitochemistry to electron microscopy, we identified main ethiologic mechanisms of cystic fibrosis. Our data demonstrate what we believe is possible to find a small molecule (adaptors and potentiators) for facilitation of DF508-CFTR trafficking to the plasma membrane. Supported by: TeleThon Grant for Cystic Fibrosis Research 2006.