Molecular Biology of Cystic Fibrosis

Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent protein kinase (PKA)- and ATP-regulated chloride channel whose activity determines the rate of electrolyte and fluid transport in a variety of epithelial tissues. Dysfunctional CFTR activity is involved in the pathogenesis of diseases including cystic fibrosis (CF), secretory diarrhea and pancreatitis. CFTR is expressed in the apical membrane of epithelial cells in tissues affected in these diseases, where its activity contributes to the transport of transepithelial salt and fluid. CFTR is thus directly involved in the pathology of at least two major diseases that cause morbidity and mortality in millions of individuals throughout the world. However, the molecular mechanisms that modulate CFTR activity in epithelial tissues are poorly understood. The development of effective treatments for these diseases would be facilitated by detailed knowledge of various cellular factors that regulate the activity of CFTR. In addition, recent evidences suggest that CFTR may exist in macromolecular complexes, in which protein-protein interactions may influence its Cl- channel activity. Identification of proteins that interact with CFTR might provide important insights into various cellular mechanisms involving CFTR. Our laboratory has isolated a number of proteins that bind to CFTR. One such protein NHERF causes a pronounced increase in CFTR channel activity. Since CF is caused by insufficient CFTR activity at the plasma membrane, a detailed understanding of CFTR?NHERF interaction could yield important clinical benefits, including possible therapeutic strategies for CF. A major goal of our laboratory is to elucidate the molecular mechanisms involved in the regulation of CFTR channel activity with a view to provide crucial insights leading to a more effective treatment for cystic fibrosis.