The Research Core headed by Dr. George Leikauf was extensively reorganized since the last application. This Core was previously called the Oxidative Stress Toxicology Core. The Oxidative Stress component was transferred to the Signal Transduction Research Core and the present Respiratory Toxicology Research Core is now focused on studies of how genetic variability in the pulmonary system modifies the effects of exposure to toxic environmental agents. The overall goal of this Core, headed by Dr. George Leikauf, is to investigate the genetic determinants and molecular mechanisms controlling pulmonary diseases induced or exacerbated by environmental agents. Research areas include the genetic basis of increased susceptibility to ozone or oxidant injury, the effects of ozone on surfactants proteins A and B, receptor G-protein coupling and other genetic determinants of asthma, gene transcription regulated by changes in oxygen concentration, and use of transgenic mouse models to study the molecular biology of pulmonary disease. Dr. Leikauf proposes to investigate the cellular and subcellular mechanisms of ozone toxicity and genetic determinants important in airway inflammation and hyperreactivity. The work involves several areas: the effects of ozonolysis products on eicosanoid and cytokine release from human airway epithelial cells; aldehyde-induced airway inflammation and hyperreactivity in mice; airway pathophysiology in transgenic mice; and the genetic determinant of ozone- or ultrafine particle-induced mortality through quantitative trait analysis. Dr. Liggett s interests are in the genetic basis of asthma and he proposes to characterize receptor structure-function relationships in G-coupled membrane proteins. A defective beta 2-adrenergic receptor (beta 2AR) may be a pathogenic factor in bronchial asthma and his research involves examining the gene encoding beta 2AR to assess the frequency of polymorphisms of this gene in normal subjects and in patients with moderate to severe asthma. Dr. McCormack proposes to investigate the role of specific structural domains of surfactant protein A (SP-A) in maintaining surface integrity in response to oxidant exposures. Transgenic mice overexpressing a mutant form of SP-A will be produced, then bred with an SP-A knockout mouse to provide for expression of the mutant SP-A in the absence of normal SP-A production. These mice will be examined for a variety of pulmonary parameters in response to oxidative stress to determine the role of specific domains of SP-A. Dr. Millhorn proposes to elucidate the cis control elements responsible for transcriptional regulation of tyrosine hydroxylase in response to reduced oxygen tension and exposure to certain metals (cobalt, nickel, lead, manganese). Preliminary work by Dr. Millhorn indicates this involves hypoxia-inducible factor (HIF-1) and AP1. Dr. Whitsett proposes to investigate mechanisms involved in respiratory epithelial function after injury. The work will focus on the role of surfactants (A, B, C, CC10). Gene targeted animals are being generated for each of these surfactant proteins, and some heterozygote animals with dysfunctionalities have been produced. In addition, humans with congenital surfactant deficiency and their heterozygote relatives have been identified.
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