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ROLE OF NRF2 IN NITRERGIC MEDIAITED STOMACH MOTILITY

Award Number: SC1GM121282
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/12/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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ROLE OF NRF2 IN NITRERGIC MEDIAITED STOMACH MOTILITY - Gastroparesis is a common complication of diabetes and can involve pathogenic oxidative stress. In rodent models, reduced nitric oxide (NO) bioavailability as a result of neuronal nitric oxide synthase (nNOS) uncoupling and increased reactive oxygen species (ROS) has been shown to play a role in delayed gastric emptying. The transcription factor nuclear factor (erythroid-derived-2)-like 2 (NRF2) regulates the expression of Phase II antioxidant and detoxification genes. Preliminary studies in rodent model of diabetes showed that the expression of NRF2 and its target genes, Gclc and Gclm, is suppressed while oxidative stress is elevated. We have demonstrated that loss of NRF2 (Nfe2/2-/-) resulted in decreased levels of tetrahydrobiopterin (BH4, a critical cofactor for nNOS dimerization and enzyme activity) and that this led to oxidative stress, uncoupling of nNOS, reduced NO levels, gastric nitrergic neuron dysfunction, and delayed gastric emptying compared to age-matched wild-type mice. These data support the notion that loss of NRF2 expression in diabetes impairs antioxidant gene expression, which deregulates NO synthesis, thereby contributing to the development of gastroparesis. We provide evidence that sex hormone, estradiol-17β (E2) mediated NRF2/nNOS expression and function is impaired in the onset of diabetes. In addition, we have shown that glycogen synthase kinase 3beta (GSK-3β) or E2 regulate the synthesis of NO in female stomachs. This data suggest that loss of NRF2 expression during hyperglycemia is a consequence of activation of a GSK-3β/CUL1/SCF/TrCP/RBX1 axis. Our central hypothesis is that nitrergic mediated gastric motility is regulated by NRF2. Specific Aim 1: will test the hypothesis that loss of NRF2 expression during hyperglycemia is a consequence of activation of a GSK-3β/CUL1/SCF/TrCP/RBX1 axis; Specific Aim 2: will test the hypothesis that restoration of NRF2 and NRF2-regulated antioxidant enzyme expression in diabetes will result in normal gastric motility and gastric emptying; and Specific Aim 3: will test the hypothesis that NRF2 and nNOS mediated gastric motility are regulated by female sex hormones; 17-estradiol (E2), progesterone and/or their gastric receptors in diabetic animals. Specific Aim 4: Investigate whether periodontal pathogens inhibit gastrointestinal (GI) motility in obese/diabetic female mice. The data from these studies will provide important information as to the mechanisms of regulation of NRF2-mediated nNOS function and thereby enhance our understanding of the pathophysiology of gastroparesis. The research outlined in these aims has translational relevance as it has the potential to identify novel treatment options for diabetes-induced gastroparesis.


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: 2024 ( Subtotal = $0 )
2024	2020	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Biomedical Research and Research Training	000	4	5/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Biomedical Research and Research Training	000	4	7/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $363,750 )
2020	2020	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Biomedical Research and Research Training	002	4	8/14/2020	NON-COMPETING CONTINUATION	$363,750
2020	2019	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Biomedical Research and Research Training	001	3	3/13/2020	NON-COMPETING CONTINUATION	$0
2020	2019	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Biomedical Research and Research Training	000	3	2/18/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $363,750

Issue Date FY: 2019 ( Subtotal = $363,750 )
2019	2019	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Biomedical Research and Research Training	000	3	8/28/2019	NON-COMPETING CONTINUATION	$363,750
														Subtotal = $363,750

Issue Date FY: 2018 ( Subtotal = $363,750 )
2018	2018	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Biomedical Research and Research Training	000	2	8/21/2018	NON-COMPETING CONTINUATION	$363,750
														Subtotal = $363,750

Issue Date FY: 2017 ( Subtotal = $356,925 )
2017	2017	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Biomedical Research and Research Training	000	1	9/12/2017	NEW	$356,925
														Subtotal = $356,925

Grand Total All Awards = $1,448,175

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ROLE OF NRF2 IN NITRERGIC MEDIAITED STOMACH MOTILITY

Award Number: SC1GM121282

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/12/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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