Oxidants have been implicated in the pathogenesis of a number of diseases and biological processes including atherosclerosis, carcinogenesis, and inflammatory disorders. Oxidants can cause cellular damage in the lung by oxidizing nucleic acids, proteins, and membrane lipids. Hyperoxia (>95 percent oxygen) can lead to inflammation and extensive impairment of respiratory function. Sufficiently long hyperoxia exposure (>3 days) is lethal. Understanding those factors that confer differential susceptibility to hyperoxic lung injury should lead to improved strategies to prevent or lessen the injury due to oxidants. Inter-species and inter-strain differences in hyperoxia-induced lung injury suggests that genetic background is an important risk factor. Among inbred mice, the C57BL/6J(B6) strain has greater responses to hyperoxia challenge than C3H/HeJ(C3). Linkage analyses have identified significant and suggestive susceptibility quantitative trait loci (QTLs) on chromosomes 2 and 3, respectively. The chromosone 2 QTL contains a strong candidate susceptibility gene, NF-E2 related factor 2 (Nrf2), which encodes an essential nuclear transcription factor (NRF-2) involved in antioxidant gene expression and regulation. Initial experimental results are consistent with a strong role for this gene in differential susceptibility to hyperoxic lkung injury. OVERALL OBJECTIVE. The overall objective of this proposal is to determine the mechanisms through which Nrf2 confers differential susceptibility to hyperoxic lung injury in inbred mice. SPECIFIC OBJECTIVES. We have designed three Specific Aims.
In Aim 1, we will determine the mechanisms through which Nrf2 expression is regulated in response to continuous hyperoxia exposure.
In Aim 2, we will utilize gene targeting and overexpression to address in vivo and in vitro the functional role of Nrf2 in the pathogenesis of hyperoxic lung injury.
In Aim 3, we will determine the effector mechanisms of Nrf2 activation in differentially hyperoxia-susceptible inbred strains of mice.
. This proposal utilizes a multi-disciplinary approach that will provide unique insight into the genetic mechanisms that determine differential susceptibility to hyperoxia-induced lung injury. Inasmuch as there is close homology between the mouse and human genomes, the identification and characterization of genes that control susceptibility to hyperoxia in this model may provide a means to characterize individuals in human populations who are at risk to oxidant lung injury, and a strategy for intervention.
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