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

概括该多PL R01是根据NCI FOA PAR-20-062共同感染和癌症提交的，包括 2个经验丰富的，合作的PI，具有微生物癌变的互补专业知识（Richard Peek和詹姆斯·福克斯）。幽门螺杆菌赋予胃腺癌的最高风险。但是，COPIS的研究其他人则证明胃微生物群会影响幽门螺杆菌协同作用的癌症风险。我们可以完全进入哥伦比亚的独特的纵向，前瞻性人类人群腺癌和幽门螺杆菌感染是地方性的。提供完整的临床，内窥镜和组织学数据在基线和每个间隔后跟进至26年，包括冷冻胃组织进行菌群分析以及从组织学上进步或保持稳定，为定义疾病机制提供了独特的机会。我们也可以访问前瞻性地从斯坦福大学的患者那里获得胃组织，有或没有预先病变，使我们将这些研究扩展到美国人口。我们的实验室开发了密切概括的模型在幽门螺杆菌和微生物群的背景下定义癌变机制的胃生态位。博士 FOX已利用无菌（GF）INS-GAS小鼠证明1）幽门螺杆菌在小鼠中加速了癌变。与GF小鼠相比，具有胃微生物群，以及2）差异化的细菌定植在高癌症和低癌症中，风险种群改变了幽门螺杆菌诱导胃损伤的能力。 Peek博士有开发复杂的原代胃体：巨噬细胞：T细胞系统，证明幽门螺杆菌驱动致癌性以细胞和应变特异性方式以及非H的信号传导。幽门螺杆菌胃物种成功地定居型号。总体而言，我们的科学范围，包括尖端代谢组学在内的可用资源以及创新的模型系统将使我们能够充分解决以下假设：胃癌的发展是不仅受到幽门螺杆菌的毒力成分的影响，而且还受到长期相互作用胃微生物群。可以调节免疫反应。我们将通过这些目标解决这一假设。目标1：在做或没有进步的人中识别并定义胃菌群的组成部分使用整个元基因组shot弹枪（WMS}测序的胃癌目标2：利用创新的离体系统来定义胃菌群和优先考虑候选人进行更确定的胃癌研究目标3：利用新型的无菌啮齿动物模型和代谢组学来定义高优先级因果关系微生物群物种和与胃生态位疾病进展相关的相应免疫反应