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PARADOXICAL ROLES OF NRF2 ACTIVATION IN ARSENIC-INDUCED BETA-CELL DYSFUNCTION

Award Number: R01ES016005
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: 09/12/2008
PERIOD OF PERFORMANCE END DATE: 05/31/2013

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PARADOXICAL ROLES OF NRF2 ACTIVATION IN ARSENIC-INDUCED BETA-CELL DYSFUNCTION - DESCRIPTION (provided by applicant) There is growing evidence that chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with the incidence of Type 2 diabetes. In contrast to what has been a prevailing beneficial view of antioxidants in preventing pancreatic ?-cell dysfunction in diabetes, this project proposes that in response to arsenic exposure, transcription factor Nrf2-mediated adaptive induction of endogenous antioxidant enzymes plays paradoxical roles in ?-cell function. The investigators hypothesize that, on the one hand, Nrf2-mediated antioxidant response blunts glucose-triggered `ROS signaling' that plays an important role in glucose-stimulated insulin secretion (GSIS); on the other hand, the response protects ?-cells from oxidative damage and subsequent apoptosis/necrosis. The investigators propose three specific aims: (1) Test the hypothesis that induction of antioxidant enzymes in response to arsenic exposure and related oxidative stress impedes glucose-triggered `ROS signaling' and thus GSIS; (2) Test the hypothesis in silico that adaptive induction of antioxidant enzymes in response to chronic oxidative stress impedes `ROS signaling', and explore intervention approaches that can improve `ROS signaling'; (3) Test the hypothesis that Nrf2-mediated antioxidant response is critical for protecting ?-cells from oxidative damage and apoptosis/necrosis induced by arsenic and/or glucose toxicity. The integrated wet-lab and computational approaches will allow to: (1) understand how environmental arsenic exposure impairs ?-cell function; (2) characterize the quantitative nature of the effect of arsenic-induced oxidative stress on `ROS signaling' that is involved in GSIS; (3) distinguish the specific roles of Nrf2 and its target antioxidant enzymes in `ROS signaling' and ?-cell function; and (4) identify novel targets and approaches to modulate insulin secretion and protect ?-cells from oxidative damage. This project will investigate the pathogenic mechanisms of Type 2 Diabetes caused by environmental arsenic exposure. The results may enable new therapeutic managements and preventive strategies for arsenic or other environmental oxidative stress-associated diabetes.


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: 2012 ( Subtotal = $436,687 )
2012	2012	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Environmental Health	000	5	5/24/2012	NON-COMPETING CONTINUATION	$436,687
														Subtotal = $436,687

Issue Date FY: 2011 ( Subtotal = $437,585 )
2011	2011	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Environmental Health	000	4	6/4/2011	NON-COMPETING CONTINUATION	$437,585
														Subtotal = $437,585

Issue Date FY: 2010 ( Subtotal = $445,501 )
2010	2010	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Environmental Health	000	3	5/6/2010	NON-COMPETING CONTINUATION	$445,501
														Subtotal = $445,501

Issue Date FY: 2009 ( Subtotal = $567,781 )
2009	2009	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Environmental Health	000	2	5/29/2009	NON-COMPETING CONTINUATION	$567,781
														Subtotal = $567,781

Issue Date FY: 2008 ( Subtotal = $570,068 )
2008	2008	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Environmental Health	000	1	9/12/2008	NEW	$570,068
														Subtotal = $570,068

Grand Total All Awards = $2,457,622

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PARADOXICAL ROLES OF NRF2 ACTIVATION IN ARSENIC-INDUCED BETA-CELL DYSFUNCTION

Award Number: R01ES016005

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: 09/12/2008

PERIOD OF PERFORMANCE END DATE: 05/31/2013

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