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Early Diagnosis/Pathogenesis of Tobacco-Related Lung Disease

Institution: Scripps Research Institute
Investigator(s): William Balch, Ph.D.
Award Cycle: 2014 (Cycle 23) Grant #: 23RT-0012 Award: $675,093
Subject Area: Early Diagnosis/Pathogenesis
Award Type: Research Project Awards

Initial Award Abstract

Chronic obstructive pulmonary disease (COPD), often a cigarette smoking-induced severe and progressive lung disease, affects millions of people and is the third leading cause of death in US. Despite its importance, there is no direct cure for COPD, and the mechanisms by which cigarette smoking triggers the disease remain largely unknown. Recently, an exciting new connection was found between COPD and the cigarette-induced dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), a protein that when mutated causes the common inherited genetic disease called cystic fibrosis (CF). Similar to people with COPD, CF patients suffer from persistent airway infection and inflammation, mucus hypersecretion, and mucus plugging of the airway do to misfolding. In this study, we will now explore the possibility that COPD is in fact a cigarette smoking-induced form of folding mismanagement. We will provide in depth insights into the mechanisms that link cigarette smoking to CFTR dysfunction through analysis of the lung cell response to CS and loss of CFTR function using genomic and proteomic technologies. We will test if a group of chemical compounds that we have found to improve the folding activity of mutant CFTR, essentially restoring lung function, can also treat the cigarette smoke-induced CFTR dysfunction, and potentially COPD. Our study will open up a new direction for clinical approaches and hopefully identify new drug targets to discover protein folding therapeutics to treat the devastating effects of cigarette smoking induced COPD.