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Abstract
Grant Number: 1F30ES014987-01 Project Title: Effects of ozone on CFTR expression and HIF signaling
PI Information: Name Title GUIMBELLOT, JENNIFER S. guim@uab.edu Abstract: DESCRIPTION (provided by applicant): Many chronic lung diseases are caused or exacerbated by environmental factors such as cigarette smoke (chronic obstructive pulmonary disease) and air pollutants including ozone. The lung epithelia provides a first line defense against many of these agents. The cystic fibrosis transmembrane conductance regulator (CFTR) serves a pivotal role in normal epithelial homeostasis, including the maintenance of normal glutathione levels in the epithelial lining fluid (ELF), a critical component of the defense against airborne toxins. In chronic lung conditions, the activation of HIP signaling pathways, such as may be caused by tissue hypoxemia, result in the down-regulation of CFTR mRNA and protein levels (as suggested by studies in cell culture and mice). Reactive oxygen species, such as those produced by ozone exposure in the lung, have been shown to activate HIF signaling pathways. CFTR deficiency results in a significantly decreased level of glutathione in the ELF, predisposing the lung to oxidant/antioxidant imbalance and additional injury from environmental toxins. The repression of CFTR by HIF signaling pathways, activated by both hypoxia and ROS from pollutants like ozone, represents a novel mechanism for lung disease pathogenesis. The goals of this proposal are to investigate 1) the specific effects of ozone on HIF signaling and CFTR expression and function and 2) the molecular mechanisms by which ROS- and hypoxia-induced HIF signaling repress CFTR.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
chloride channel, environmental exposure, gene environment interaction, hypoxia inducible factor 1, lung ischemia /hypoxia, membrane activity, ozone, respiratory epithelium
air pollution, free radical oxygen, gene induction /repression, glutathione, oxidizing agent, protein structure function, respiratory disorder, respiratory toxin
chromatin immunoprecipitation, electrophysiology, immunocytochemistry, laboratory mouse, predoctoral investigator
Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM 1530 3rd Avenue South BIRMINGHAM, AL 35294 Fiscal Year: 2006 Department: MEDICINE Project Start: 15-JUL-2006 Project End: 14-JUL-2009 ICD: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES IRG: ZRG1