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NRF Transcription Factors in Environmental Stress and Disease Intervention

Award Number: R35ES031575
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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NRF Transcription Factors in Environmental Stress and Disease Intervention - 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 Furthermore, recent unpublished work from my lab has indicated that prolonged upregulation of NRF2 may also contribute to the diabetogenic effects of arsenic.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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,154,486 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Environmental Health	000	7	2/12/2026	NON-COMPETING CONTINUATION	$1,154,486
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Environmental Health	001	7	4/6/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,154,486

Issue Date FY: 2025 ( Subtotal = $1,157,198 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Environmental Health	001	6	3/11/2025	NON-COMPETING CONTINUATION	$1,157,198
2025	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	000	4	12/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,157,198

Issue Date FY: 2024 ( Subtotal = $1,160,110 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Environmental Health	000	5	4/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,160,110
														Subtotal = $1,160,110

Issue Date FY: 2023 ( Subtotal = $908,897 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	001	4	8/15/2023	NON-COMPETING CONTINUATION	$0
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	000	4	2/28/2023	NON-COMPETING CONTINUATION	$908,897
														Subtotal = $908,897

Issue Date FY: 2022 ( Subtotal = $911,114 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	000	3	2/23/2022	NON-COMPETING CONTINUATION	$911,114
														Subtotal = $911,114

Issue Date FY: 2021 ( Subtotal = $918,204 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	000	2	2/17/2021	NON-COMPETING CONTINUATION	$918,204
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	001	2	9/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $918,204

Issue Date FY: 2020 ( Subtotal = $893,829 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	000	1	5/26/2020	NEW	$893,829
														Subtotal = $893,829

Grand Total All Awards = $7,103,838

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NRF Transcription Factors in Environmental Stress and Disease Intervention

Award Number: R35ES031575

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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