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Aryl hydrocarbon receptor-mediated differential gene regulation - Mechanism of stanniocalcin 2 mediated protection against NAFLD

Award Number: R01DK122028
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT The Aryl Hydrocarbon Receptor (AhR) is a member of the Per-Arnt-Sim (PAS) domain protein family that regulates adaptive and toxic responses to a variety of chemical pollutants, including polycyclic aromatic hydrocarbons and halogenated aromatic hydrocarbons, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We observed that the newly identified endogenous AhR agonist, cinnabarinic acid (CA) does not upregulate prototypical AhR target gene, Cyp1a1 and is not involved in xenobiotic regulation. On contrary, CA induced expression of a novel AhR target gene, stanniocalcin 2 (Stc2) in liver. Our studies indicate that in response to CA-treatment, AhR interacted dichotomously to xenobiotic response elements (XREs, 5'-GCGTG- 3') present within the Stc2 promoter regulating its expression. Additionally, this proposal capitalizes on our recent observation that CA treatment protected against non-alcoholic fatty liver disease in an AhR-dependent manner. The in vitro model that mimics fatty liver disease, showed significant role of STC2 in CA-specific AhR- driven hepatoprotection. Moreover, we recently constructed hepatocyte-specific Stc2 conditional knockout mice (Stc2-hKO) which showed exacerbated hepatic steatosis and metabolic deterioration. The studies proposed in this renewal application are logical extension of our current award and hypothesize that the CA- specific AhR-regulated hepatic STC2 signaling plays critical role in attenuation of lipogenesis resulting in protection against non-alcoholic fatty liver disease. Using the Stc2-hKO mice, Specific Aim 1 of this application will investigate role of in vivo STC2 signaling in AhR-mediated protection against steatohepatitis in response to CA treatment. Specific Aim 2 will utilize lipidomics and single-nuclei transcriptomics to characterize CA-specific STC2 mediated hepatoprotective pathways involved in the mitigation of lipogenesis. Specific Aim 3 will investigate AhR-mediated regulation of Stc2 promoter in non-alcoholic fatty liver disease. The current application will unravel mechanism of transcription regulation of Stc2 by CA-specific AhR activation and characterize its significance against non-alcoholic fatty liver disease.


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 = $315,375 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	1/12/2024	COMPETING CONTINUATION	$315,375
														Subtotal = $315,375

Issue Date FY: 2023 ( Subtotal = $261,000 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	4/13/2023	NON-COMPETING CONTINUATION	$261,000
														Subtotal = $261,000

Issue Date FY: 2022 ( Subtotal = $261,000 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/20/2022	NON-COMPETING CONTINUATION	$261,000
														Subtotal = $261,000

Issue Date FY: 2021 ( Subtotal = $247,723 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	4/29/2021	NON-COMPETING CONTINUATION	$261,000
2021	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	12/8/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$148,089
2021	2020	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/8/2020	NON-COMPETING CONTINUATION	-$161,366
2021	2020	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	5/6/2021	NON-COMPETING CONTINUATION	-$116,560
2021	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	3	5/6/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$116,560
														Subtotal = $247,723

Issue Date FY: 2020 ( Subtotal = $284,400 )
2020	2020	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/24/2020	NON-COMPETING CONTINUATION	$284,400
														Subtotal = $284,400

Issue Date FY: 2019 ( Subtotal = $284,400 )
2019	2019	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/11/2019	NEW	$284,400
														Subtotal = $284,400

Grand Total All Awards = $1,653,898

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Aryl hydrocarbon receptor-mediated differential gene regulation - Mechanism of stanniocalcin 2 mediated protection against NAFLD

Award Number: R01DK122028

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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