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Interactions Between the Microbiota and Helicobacter pylori in Gastric Carcinogenesis

微生物群与幽门螺杆菌在胃癌发生中的相互作用

基本信息

批准号：
10709135
负责人：
JAMES G FOX
金额：
$ 69.97万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709135
关键词：
Acceleration Address Adenocarcinoma Affect Antibiotic Therapy Antibiotics Atrophic Gastritis Attenuated Bacteria Biological Models Cancer Etiology Carcinogenesis Mechanism Cells Cessation of life Chromosomal Instability Chronic Clinical Clinical Data Colombia Colombian Complement Complex DNA Data Development Diagnosis Disease Disease Management Disease Progression Dysplasia Etiology Female Freezing Gases Gastric Adenocarcinoma Gastric Intestinal Type Adenocarcinoma Gastric Intraepithelial Neoplasia Gastric Tissue Gastritis Germ-Free Helicobacter Infections Helicobacter pylori High-Risk Cancer Hispanic Histologic Histology Human Immune response Incidence Individual Inflammatory Response Injury Intestinal Metaplasia Intestines Laboratories Lesion Link Macrophage Malignant - descriptor Malignant Neoplasms Mediating Modeling Mus Neoplasms Oncogenic Patients Persons Population Publishing Resources Risk Rodent Model Seasons Section 8 Shotgun Sequencing Shotguns Signal Transduction Stomach Structure System T-Lymphocyte Testing Time Transplantation United States Virulence cancer risk carcinogenesis carcinogenicity clinical investigation co-infection cohort disorder risk dysbiosis follow-up gastric carcinogenesis gastric microbiota gastric organoids high risk high risk population immunoregulation improved in vivo innovation male malignant stomach neoplasm member metabolomics metagenome microbial microbial community microbiota mortality novel pathogen premalignant prospective response synergism targeted treatment

项目摘要

Summary This multi-Pl R01 is submitted in response to NCI FOA PAR-20-062 Co-infection and Cancer and includes 2 seasoned, collaborative Pis with complementary expertise in microbial carcinogenesis (Richard Peek and James Fox). H. pylori confers the highest known risk for gastric adenocarcinoma. However, studies by the CoPis and others have demonstrated that gastric microbiota populations affect cancer risk in synergy with H. pylori. We have full access to a unique longitudinal, prospective human cohort in Colombia where gastric adenocarcinoma and H. pylori infections are endemic. Full clinical, endoscopic, and histologic data are available at baseline and at each interval follow-up out to 26 years, including frozen gastric tissue for microbiota analysis and culture from the 20- and 26-year timepoints from persons who either progressed histologically or remained stable, providing a unique opportunity to define disease mechanisms. We also have access to prospectively obtained gastric tissue from patients at Stanford with or without premalignant lesions, allowing us to extend these studies into a US population. Our laboratories have developed models that closely recapitulate the gastric niche to define mechanisms of carcinogenesis within the context of H. pylori and the microbiota. Dr. Fox has utilized germ-free (GF) INS-GAS mice to demonstrate 1) H. pylori accelerates carcinogenesis in mice harboring a gastric microbiota compared to GF mice, and 2) colonization with bacteria differentially represented in high vs. low cancer risk populations modifies the ability of H. pylori to induce gastric injury. Dr. Peek has developed complex primary gastroid:macrophage:T cell systems to demonstrate that H. pylori drives oncogenic signaling in a cell- and strain-specific manner and that non-H. pylori gastric species successfully colonize these models. Collectively, our scientific scope, available resources including cutting-edge metabolomics, and innovative model systems will allow us to fully address the hypothesis that progression to gastric cancer is influenced not only by H. pylori virulence constituents, but also by prolonged interactions with members of the gastric microbiota. which can modulate immune responses. We will address this hypothesis via these Aims. Aim 1: Identify and define components of the gastric microbiota in persons who did or did not progress towards gastric cancer using Whole Metagenome Shotgun (WMS} sequencing Aim 2: Utilize innovative ex vivo systems to define the carcinogenic potential of gastric microbiota species and prioritize candidates for more definitive in vivo studies of gastric cancer Aim 3: Utilize novel germ-free rodent models and metabolomics to define causality of high priority gastric microbiota species and corresponding immune responses linked to disease progression within the gastric niche

总结