Title: NRF transcription factors in Environmental Stress and Disease Intervention
PROJECT SUMMARY
My broad research program includes in-depth mechanistic investigations of arsenic pathogenesis/NRF
signaling and the translation of basic mechanistic knowledge to preclinical drug development. Chronic
exposure to arsenic, an environmental contaminant that affects an estimated 160 million people worldwide, is a
global public health concern correlated with an increased risk of developing certain types of cancer, as well as
type II diabetes. However, a critical gap still exists in our knowledge concerning the precise pathologic
mechanisms of arsenic, and generation of viable therapeutic approaches. Over the past decade, my research
has 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 systems—specifically the NRF2
response—to alleviate the damage or pathogenesis induced by arsenic. Transcription factor NRF2 controls the
cellular stress response following exposure to environmental insults. Since the discovery of the NRF2 pathway
in 1999, NRF2 has been viewed as a “good” transcription factor that protects against oxidative stress-related
diseases, including cancer, and controlled activation of NRF2 using NRF2-inducing compounds to prevent
cancer initiation is well recognized. However, in 2008 my lab unveiled the “dark side” of NRF2—uncontrolled
NRF2 activation is a driver of cancer progression, metastasis, and resistance to therapy. Furthermore, recent
unpublished work from my lab has indicated that prolonged upregulation of NRF2 may also contribute to the
diabetogenic effects of arsenic. Therefore, specific NRF2 inhibitors will be powerful probes for dissecting the
“dark side” role of NRF2 in disease. A big challenge in the field is that there are no NRF2-specific inhibitors
available despite the efforts made.
Therefore, the key scientific questions that need to be addressed, and as such are the focus of this R35
proposal, include: (i) the molecular basis of diseases associated with arsenic exposure (focusing on lung
cancer and type II diabetes); (ii) the effects of environmental stress on the NRF2 signaling network; (iii) the
ways by which we can harness the NRF2 response to improve human health; and (iv) the distinct roles of the
cap'n'collar (CNC) family members NRF1, NRF2, and NRF3. My lab will pursue answers to these questions
through innovative and rigorous experimental approaches, which will allow us to fill current gaps, advance
environmental health research, and ultimately improve human health.