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FUNCTION OF MST4-EZRIN-ACAP4 SIGNALING IN GASTRIC PARIETAL CELL SECRETION AND HOMEOSTASIS

Award Number: R01DK115812
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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The digestive function of the stomach depends on acidification of the gastric lumen. Acid secretion into the lumen is triggered by activation of a cAMP-dependent protein kinase (PKA) cascade, which ultimately results in the insertion of gastric H,K-ATPases into the apical plasma membranes of parietal cells. A coupling protein is ezrin, an 80 kDa phosphoprotein, whose phosphorylation at Ser66 by PKA is required for parietal cell activation. Our early study demonstrated that H. pylori VacA perturbs parietal cell secretion and induces parietal cell loss via calpain-elicited ezrin proteolysis. Recent studies demonstrate that gastric metaplasia and hyperplasia are results of ezrin loss in the parietal cells, suggesting the importance of ezrin signaling in parietal cell homeostasis and renewal. However, little is known regarding the molecular mechanism(s) by which the ezrin signaling pathway operates in gastric acid secretion and responds to H. pylori infection. The long-term goal of our research is to delineate how ezrin functions in gastric parietal cell secretion and homeostasis in response to the physiological stimulation and to H. pylori infection. To address this question, three Specific Aims are proposed: first, we will evaluate how MST4 interacts with ACAP4 and ezrin using epitope-tagging and chemical footprinting approaches. These studies will involve a detailed analysis of the structural determinants that mediate a direct MST4-ACAP4 contact. Binding domain data will be used to design peptides that potently and specifically perturb MST4-ACAP4 interactions in in vitro binding assays. The function of this interaction will then be evaluated by the effects of the peptides on acid secretion using permeabilized gastric glands and by introducing MST4-interaction deficient ACAP4 mutants into cultured parietal cells from ACAP4 knock-out animals. Second, we will define the role of MST4 in regulating spatiotemporal dynamics of ARF6 GTPase during parietal cell activation. The importance of such an interaction in acid secretion in response to physiological stimulation of H. pylori infection will then be evaluated by functional assay and super-resolution imaging analysis. Third, we plan to illustrate the molecular mechanisms by which MST4-ezrin-ACAP4 signaling axis orchestrates parietal cell homeostasis in human gastric organoids in the presence of H. pylori infection. These studies will be facilitated by biochemical and functional characterization coupled with optical imaging of secretory vesicle trafficking in live parietal cells with novel ACAP4 inhibitor MSM0601. Studying the molecular mechanisms underlying parietal cell secretion and homeostasis is of great significance in understanding the cellular physiology of regulated epithelial secretion in the gut, and is also expected to be of great benefit in leading to development of pharmacological strategies for correction and/or prevention of H. pylori infection-elicited gastric atrophy.


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: 2023 ( Subtotal = $0 )
2023	2019	THE MOREHOUSE SCHOOL OF MEDICINE, INC.	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$9,098 )
2022	2019	MOREHOUSE SCHOOL OF MEDICINE, INC.	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/16/2022	NON-COMPETING CONTINUATION	-$9,098
														Subtotal = -$9,098

Issue Date FY: 2019 ( Subtotal = $322,340 )
2019	2019	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	9/5/2019	NON-COMPETING CONTINUATION	$0
2019	2019	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/23/2019	NON-COMPETING CONTINUATION	$322,340
														Subtotal = $322,340

Issue Date FY: 2018 ( Subtotal = $322,340 )
2018	2018	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/31/2018	NON-COMPETING CONTINUATION	$322,340
														Subtotal = $322,340

Issue Date FY: 2017 ( Subtotal = $322,340 )
2017	2017	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/19/2017	NEW	$322,340
														Subtotal = $322,340

Grand Total All Awards = $957,922

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FUNCTION OF MST4-EZRIN-ACAP4 SIGNALING IN GASTRIC PARIETAL CELL SECRETION AND HOMEOSTASIS

Award Number: R01DK115812

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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