The group’s linkage analyses have identified the transcription factor Nrf2 as a critical determinant of susceptibility to hyperoxic lung injury in the mouse. Nrf2 forms heterodimers with small Maf proteins and the heterodimers bind to antioxidant response elements (AREs) to regulate gene transcription (see figure below). One of the objectives of this project is to determine the mechanisms through which Nrf2 confers differential susceptibility to oxidant-induced lung injury in inbred mice. The group has pursued this objective using in vivo animal models and in vitro cell culture systems.
These studies have led to the identification of effector genes (e.g. NQO1) and pathways that are modulated by NRF2. Through collaboration with the Environmental Genomics Group led by Douglas Bell, Ph.D., Kleeberger and group members are developing computational algorithms to identify polymorphic antioxidant response elements (ARE) in oxidant-mediated genes. The group has also begun to investigate the role of Nrf2 in fibrotic lung injury induced by bleomycin. Importantly, the group has been working to translate its investigations in animal models to human populations, and has resequenced NRF2 and identified functional single nucleotide polymorphisms (SNPs). In collaboration with extramural investigators, the Environmental Genetics Group is evaluating the role of these SNPs, and SNPs in NRF2 effector genes (e.g. NQO1) in a number of diseases including RSV infection and chronic lung disease in infants, and acute respiratory distress syndrome (ARDS) in acute lung injury patients.
Ongoing Projects in the Laboratory: