Mechanisms of Injury and Adaptation

Covalent modification and oxidation of protein sensor-triggers initiates signaling cascades that contribute to injury and to the induction of adaptive stress responses. We are studying the mechanisms by which electrophile adduction of the thiol-rich sensor protein Keap1 regulates the activation of the transcription factor Nrf2, which controls cellular stress responsive genes. We also are characterizing the roles of modification of putative sensor proteins in mitochondria, cytoplasm, nuclei and endoplasmic reticulum in triggering specific signaling pathways that lead to stress responses and cell death. Other studies are focused on the identification of proteins that recognize adducted proteins and direct them to degradation via the ubiquitin-proteasome system.