The Role of NRF2 and Related Genes in Susceptibility to Lung Injury and Disease

Environmental Genetics

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.

Nrf2-antioxidant defense system in airway cells. In normal physiologic conditions (A), a balance between antioxidants and oxidants maintains cellular redox equilibrium. Under stressed condition (B), oxidative stimuli could accelerate ROS production, directly or indirectly, and activate Nrf2 for production of ARE-driven antioxidants, while overwhelming ROS over antioxidant capacity may cause oxidative injury leading to pulmonary pathologic symptoms. (From Cho et al., Antioxidant Redox Signal, 2006)

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:

• Mechanisms of Nrf2-mediated protection against oxidant-induced lung injury
• Functional polymorphisms in human NRF2 and the risk of oxidative stress-induced diseases
• Computational methods to identify polymorphic AREs in putative oxidant-mediated genes
• Investigation of the role of NQO1 (NAD(P)H quinone oxidoreductase 1) in acute lung injury and ARDS

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