Title: NRF transcription factors in Environmental Stress and Disease InterventionPROJECT SUMMARY My broad research program includes in-depth mechanistic investigations of arsenic pathogenesis/NRFsignaling and the translation of basic mechanistic knowledge to preclinical drug development. Chronicexposure to arsenic an environmental contaminant that affects an estimated 160 million people worldwide is aglobal public health concern correlated with an increased risk of developing certain types of cancer as well astype II diabetes. However a critical gap still exists in our knowledge concerning the precise pathologicmechanisms of arsenic and generation of viable therapeutic approaches. Over the past decade my researchhas revealed that dysregulation of the NRF2 signaling pathway is a key driver of arsenic-based pathologies. Accordingly my overarching vision is to harness our body's defense systemsspecifically the NRF2responseto alleviate the damage or pathogenesis induced by arsenic. Transcription factor NRF2 controls thecellular stress response following exposure to environmental insults. Since the discovery of the NRF2 pathwayin 1999 NRF2 has been viewed as a good transcription factor that protects against oxidative stress-relateddiseases including cancer and controlled activation of NRF2 using NRF2-inducing compounds to preventcancer initiation is well recognized. However in 2008 my lab unveiled the dark side of NRF2uncontrolledNRF2 activation is a driver of cancer progression metastasis and resistance to therapy. Furthermore recentunpublished work from my lab has indicated that prolonged upregulation of NRF2 may also contribute to thediabetogenic effects of arsenic. Therefore specific NRF2 inhibitors will be powerful probes for dissecting thedark side role of NRF2 in disease. A big challenge in the field is that there are no NRF2-specific inhibitorsavailable despite the efforts made. Therefore the key scientific questions that need to be addressed and as such are the focus of this R35proposal include: (i) the molecular basis of diseases associated with arsenic exposure (focusing on lungcancer and type II diabetes); (ii) the effects of environmental stress on the NRF2 signaling network; (iii) theways by which we can harness the NRF2 response to improve human health; and (iv) the distinct roles of thecap'n'collar (CNC) family members NRF1 NRF2 and NRF3. My lab will pursue answers to these questionsthrough innovative and rigorous experimental approaches which will allow us to fill current gaps advanceenvironmental health research and ultimately improve human health.