权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Defining Inflammatory Triggers that Induce Diverse Subtypes of Gastric Metaplasia

定义诱发胃化生不同亚型的炎症触发因素

基本信息

批准号：
10604888
负责人：
Stella Garden Hoft
金额：
$ 5.27万
依托单位：
SAINT LOUIS UNIVERSITY
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：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604888
关键词：
Adenocarcinoma Affect Animals Autoimmune Autoimmunity Bacterial Infections Biopsy Cancer Burden Cancer Etiology Cells Cessation of life Chronic Chronic Gastritis Classification Complex Cytokine Signaling Cytotoxin Development Diagnosis Disease Disease Progression Epithelial Cells Equation Etiology Gastric Adenocarcinoma Gastric Metaplasia Gastritis Gene Expression Profile Genetically Engineered Mouse Goals Helicobacter Infections Helicobacter pylori Human Hypersensitivity IL4R gene Individual Infection Inflammation Inflammatory Interleukin-13 Interleukin-4 Intervention Knowledge MEKs Malignant Neoplasms Medical Metaplasia Metaplastic Cell Methods Modeling Molecular Molecular Analysis Molecular Profiling Mus Oncogenic Outcome Pathologic Patients Phenotype Precancerous Conditions Predisposition Prevention Prevention strategy Recombinants Reporting Research Resolution Risk Risk Factors Screening for Gastric Cancer Severities Signal Induction Signal Pathway Signal Transduction Stomach Neoplasms Testing Therapeutic Intervention Tissue Sample Tissues Work accurate diagnosis atopy autoimmune gastritis cancer subtypes cytokine cytotoxic gastric carcinogenesis high risk human disease human tissue improved individualized medicine innovation insight malignant stomach neoplasm molecular phenotype molecular subtypes mortality mouse model new therapeutic target novel novel therapeutic intervention premalignant programs receptor response risk stratification screening single-cell RNA sequencing spasmolytic polypeptide surveillance strategy survival outcome targeted treatment transcriptomics treatment strategy tumor progression

项目摘要

PROJECT SUMMARY Chronic gastritis initiates a pathological progression of disease which in some individuals culminates in gastric cancer, the fourth leading cause of cancer related mortality worldwide. Helicobacter pylori infection is the most common cause of gastritis and responsible for most gastric cancer cases worldwide. Autoimmune gastritis is another prominent cause of gastritis increasing the risk of gastric cancer development. Persistent gastric inflammation initiates the transformation of healthy epithelial cells into pre-cancerous metaplastic cells which transform into adenocarcinoma in a subset of individuals. Recent transcriptomic analyses of gastric adenocarcinoma have led to the identification of four distinct molecular subtypes. This discovery has improved targeted treatment and surveillance strategies for each distinct gastric cancer subtype. Currently, there is a need for an in-depth molecular analysis of pre-cancerous gastric metaplasia. We recently discovered that gastric metaplasia can also take on distinct molecular phenotypes in the autoimmune setting. It needs to be determined whether metaplasia arising out of H. pylori infection, known to inject cytotoxins that can interfere with cell- signaling pathways possibly promoting oncogenic transformation, is phenotypically distinct from metaplasia arising out of autoimmune gastritis. If metaplastic subtypes are conserved, then chronic inflammatory signals, independent of etiology, likely contribute to cancer progression; however, if metaplastic subtypes in infection are distinct from autoimmunity, then factors unique to the bacterial infection likely drive an alternative trajectory of oncogenic transformation. Furthermore, how certain inflammatory cytokines (e.g., IL-4/IL-13) impact the development of gastric metaplasia and specific molecular subtypes of metaplasia needs to be established. Identifying molecular phenotypes of pre-cancerous metaplastic cells, in distinct disease settings, that may carry differential oncogenic potentials, will contribute to the discovery of novel screening targets to decrease the gastric cancer burden in highly susceptible individuals. Identifying the inflammatory signals that promote the development of potentially high-risk metaplastic cells will aid in discovery of new therapeutic strategies for inhibiting gastric cancer. In this proposal, metaplasia arising out of two common etiologies of gastritis, H. pylori infection and autoimmune gastritis, will be molecularly defined and compared. Gastric metaplasia from human gastritis patients will be transcriptionally profiled to determine the phenotypes of metaplasia induced by human disease. The impact of inflammatory cytokines, IL-4 and IL-13, on inducing/expanding phenotypically distinct subtypes of gastric metaplasia will also be determined. This work will improve the mechanistic understanding of gastric carcinogenesis in the settings of H. pylori infection and autoimmune gastritis. This knowledge can then be used to improve medical prevention strategies and identify novel targets for therapeutic intervention of gastric cancer.

项目总结