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Role of Protein Kinase A (PKA)-mediated mesenchymal-epithelial crosstalk in gastric preneoplasia

Award Number: R16GM149389
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: 07/17/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Role of Protein Kinase A (PKA)-mediated mesenchymal-epithelial crosstalk in gastric preneoplasia - Project Summary According to the American Society of Clinical Oncology, in the year 2020, stomach cancer caused death of 768,793 patients worldwide making it the fourth leading cause of cancer deaths. H. pylori infection is the strongest risk factor for gastric cancer. H. pylori-initiated inflammation leads to atrophic gastritis, spasmolytic polypeptide expressing metaplasia (SPEM), gastric intestinal metaplasia (GIM) and dysplasia, a series of preneoplastic lesions strongly associated with gastric cancer. The eradication of H. pylori by antibiotic treatment has been effective in reducing the incidence of preneoplastic lesions and gastric cancer. However, following H. pylori eradication already established mucosal metaplastic changes may not reverse, and the risk of gastric cancer in such patients remains high. A better understanding of the mechanisms contributing to inflammation and the resulting preneoplastic lesions is required to develop rational and effective therapies. One of the mechanisms by which H. pylori stimulates inflammatory signaling and preneoplastic lesions is by disrupting the communication between the gastric epithelium and the surrounding mesenchyme/stroma. We have identified a novel role of PKA activation in the gastric mesenchyme in establishing a proinflammatory and preneoplastic state that is associated with downregulation of BMP signaling which is known to be a key regulator of gastric inflammation and preneoplasia. We generated and characterized a novel conditional mutant mouse Six2Cre+/-- PKAcRfl/wt (CA-PKA) model in which single allele-mediated expression of constitutively active PKA (PKAcR) was induced in the stomach mesenchyme using Six2-Cre transgenic mice. CA-PKA Mice develop preneoplastic lesions such as atrophic gastritis, SPEM, GIM and dysplasia along with marked chronic inflammation, factors strongly associated with gastric cancer The central hypothesis of this proposal is that PKA activation in the gastric mesenchyme is a key driver of gastric carcinogenesis by inciting inflammation and inhibiting BMP signaling that will be tested in the following three aims. Aim 1 is to determine the mechanisms that contribute to inflammation and oxyntic atrophy in CA-PKA mice. Aim 2 is to determine the effects of genetic modulation of BMP pathway inhibitor gremlin 1 (Grem1) on the severity of gastric preneoplastic lesions in CA-PKA mice. Aim 3 is to determine the impact of misregulated PKA signaling on H. felis-induced gastric pathology. Expected outcomes of the proposed research will define the molecular and functional significance of mis-regulated PKA signaling in disrupting gastric homeostasis and driving pathology. A better understanding of misregulated PKA signaling as an underlying cause of gastric inflammation and preneoplasia can help develop preventative and treatment strategies for gastric cancer and associated pathological conditions.


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 = $147,000 )
2025	2025	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Biomedical Research and Research Training	000	3	4/15/2025	NON-COMPETING CONTINUATION	$147,000
														Subtotal = $147,000

Issue Date FY: 2024 ( Subtotal = $239,600 )
2024	2024	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Biomedical Research and Research Training	000	2	4/30/2024	NON-COMPETING CONTINUATION	$139,950
2024	2024	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Biomedical Research and Research Training	001	2	8/5/2024	SUPPLEMENT FOR EXPANSION	$99,650
														Subtotal = $239,600

Issue Date FY: 2023 ( Subtotal = $147,000 )
2023	2023	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Biomedical Research and Research Training	000	1	7/14/2023	NEW	$147,000
														Subtotal = $147,000

Grand Total All Awards = $533,600

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Role of Protein Kinase A (PKA)-mediated mesenchymal-epithelial crosstalk in gastric preneoplasia

Award Number: R16GM149389

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: 07/17/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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