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

蛋白激酶 A (PKA) 介导的间充质-上皮串扰在胃肿瘤前期的作用

• 批准号: 10627168
• 负责人: Pawan Puri
• 金额: $ 14.7万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-17 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627168
• 关键词: Adenocarcinoma; Alleles; American Society of Clinical Oncology; Anti-Inflammatory Agents; Antibiotic Therapy; Atrophic; Atrophic Gastritis; Automobile Driving; Biomedical Research; Bone Morphogenetic Proteins; Cancer Etiology; Cancerous; Cause of Death; Cells; Cessation of life; Chronic; Communication; Cyclic AMP-Dependent Protein Kinases; Data; Down-Regulation; Epithelial-Stromal Communication; Epithelium; Gastric Adenocarcinoma; Gastric Parietal Cells; Gastritis; Genetic; Gland; Growth; Helicobacter; Helicobacter Infections; Helicobacter felis; Helicobacter pylori; Homeostasis; Hyperplasia; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Intestinal Intraepithelial Neoplasia; Lesion; Ligands; Mediating; Mesenchymal; Mesenchyme; Messenger RNA; Metaplasia; Modeling; Molecular; Mucous Membrane; Mucous body substance; Mus; Mutant Strains Mice; Neoplasms; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Phosphorylation; Predisposition; Preneoplastic Conditions; Prevention strategy; Proliferating; Proteins; Research; Risk; Risk Factors; Role; STAT3 gene; Series; Severities; Signal Transduction; Signaling Protein; Stimulus; Stomach; Stromal Cells; Students; Testing; Tissues; Training; Transgenic Mice; Transgenic Organisms; Universities; Up-Regulation; antagonist; conditional mutant; constitutive expression; cytokine; effective therapy; experimental study; gastric carcinogenesis; gastric intestinal metaplasia; gastric pre-neoplasia; high risk; inflammatory milieu; inhibitor; malignant stomach neoplasm; minority student; neoplastic; novel; overexpression; premalignant; prevent; promoter; spasmolytic polypeptide; synergism; treatment strategy; tumor

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.

项目总结