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.

项目摘要慢性胃炎引发了疾病的病理进展，在某些个体中，胃癌是全球癌症与死亡率相关的第四个主要原因。幽门螺杆菌感染是胃炎的最常见原因，并导致全球大多数胃癌病例。自身免疫性胃炎是胃炎的另一个显着原因，增加了胃癌发展的风险。持续的胃炎症会引发健康上皮细胞转化为癌前塑性细胞，该细胞转化转变为一个个体一部分的腺癌。最近对胃的转录组分析腺癌已导致鉴定出四种不同的分子亚型。这个发现有所改善针对每种不同胃癌亚型的目标治疗和监视策略。目前，有需要用于对癌前胃化生的深入分子分析。我们最近发现胃 Metaplasia还可以在自身免疫性设置中采用不同的分子表型。它需要确定是否由幽门螺杆菌感染引起的转移，已知可以干扰细胞的细胞毒素信号通路可能促进致癌转化，在表型上与化生不同由自身免疫性胃炎产生。如果保守化型亚型，则慢性炎症信号，独立于病因，可能导致癌症进展。但是，如果感染中的化生亚型是不同于自身免疫性，然后细菌感染所特有的因素可能会推动致癌转化。此外，某些炎症细胞因子（例如IL-4/IL-13）如何影响需要建立胃化生的发展和特定的分子亚型。在不同的疾病环境中，鉴定癌前化生细胞的分子表型，可能携带差异性致癌潜力将有助于发现新型筛选目标以减少胃高度易感人士的癌症负担。确定促进炎症信号开发潜在的高风险转移细胞将有助于发现新的治疗策略抑制胃癌。在此提案中，由两种常见的胃炎病因，幽门螺杆菌感染和自身免疫性胃炎将得到分子定义和比较。人类胃炎的胃代理患者将进行抄写，以确定由人类疾病引起的化生的表型。炎症细胞因子IL-4和IL-13的影响对诱导/扩展的表型不同的亚型的影响还将确定胃化生。这项工作将提高对胃的机械理解幽门螺杆菌感染和自身免疫性胃炎的环境中的致癌作用。然后可以使用这些知识改善医疗预防策略并确定胃癌治疗干预的新颖靶标。