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Defining GATA4's Molecular Function in Gastric Cell Biology

Award Number: R01DK134064
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Defining GATA4's Molecular Function in Gastric Cell Biology - SUMMARY Gastric parietal cells (PCs) play a critical role in GI function by secreting acid for digestion and protection against infection and by synthesizing growth factors that influence the development of other cell types including zymogenic chief cells. Although there has been longstanding interest in defining PC biology and gastric acid secretion dating back to the 1800s, PCs have been challenging to study. PC dysfunction, including acid hypersecretion or hyposecretion, underlies a range of human diseases associated with a high socioeconomic burden including chronic gastritis, drug-related peptic ulcer disease, Helicobacter pylori related peptic ulcer disease, and cancer. For example, peptic ulcer disease affects more than 4 million people in the US each year with 1 in 10 persons experiencing an ulcer at least once, and gastric cancer is the third leading cause of cancer related deaths worldwide. Given the essential role for PCs in maintaining a healthy stomach, it is surprising that a comprehensive understanding of the molecular programs that regulate and maintain normal PC differentiation and function, and thereby PC health and overall gastric epithelial cell health, is incomplete. Our finding that the transcription factor GATA4 binds to the regulatory regions—enhancers and promoters—of 81% of gene set defined as being uniquely expressed in PCs sheds light on the PC knowledge gap, implicating GATA4 as a crucial principal regulator of PC biology. The goal of this proposal is to test the central hypothesis that GATA4 is required to maintain homeostasis of the mature gastric epithelium by directly controlling the gene expression program defining PC function. Studies in Aim 1 will define the mechanistic contribution of GATA4 to PC function using a conditional mouse model to delete GATA4 in PCs and a suite of morphological and molecular investigative tools. Studies in Aim 2, using a Gata4 conditional knock-in model uniquely available in our lab to overexpress GATA4 in PCs in conjunction with gastric injury, will provide evidence to determine the extent to which GATA4 loss is necessary for PC dysfunction and downstream metaplasia. We will also examine the contribution of GATA4 promoter hypermethylation to PC dysfunction and metaplasia. Finally, studies in Aim 3 will apply findings from the mouse to human PC biology using human gastric organoids to determine the extent to which GATA4 function in PCs is evolutionarily conserved. Overall, we expect our studies to elucidate GATA4-dependent molecular pathways essential to maintain PC function and health and that, when disrupted, cause PC dysfunction and gastric disease. Discoveries of fundamental cellular and molecular mechanisms, in this case those underpinning normal gastric epithelial cell homeostasis, can provide prerequisite knowledge to apply to future clinical applications for gastric diseases including gastritis, peptic ulcer disease, metaplasia, and cancer.


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: 2025 ( Subtotal = $512,472 )
2025	2025	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/16/2025	NON-COMPETING CONTINUATION	$512,472
														Subtotal = $512,472

Issue Date FY: 2024 ( Subtotal = $508,824 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$508,824
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	8/13/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$390,114
2024	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/30/2024	NON-COMPETING CONTINUATION	$0
2024	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	8/13/2024	NON-COMPETING CONTINUATION	-$390,114
														Subtotal = $508,824

Issue Date FY: 2023 ( Subtotal = $521,650 )
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/19/2023	NON-COMPETING CONTINUATION	$521,650
														Subtotal = $521,650

Issue Date FY: 2022 ( Subtotal = $535,650 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/1/2022	NEW	$535,650
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/3/2022	NEW	$0
														Subtotal = $535,650

Grand Total All Awards = $2,078,596

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Defining GATA4's Molecular Function in Gastric Cell Biology

Award Number: R01DK134064

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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