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

• 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
• 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

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 慢性胃炎引发疾病的病理进展，在某些个体中， 胃癌是全球癌症相关死亡率的第四大原因。幽门螺杆菌感染是什么？ 是胃炎的最常见原因，也是全球大多数胃癌病例的原因。自身免疫性胃炎 是胃炎增加胃癌发展风险的另一个重要原因。胃潴留 炎症引发健康上皮细胞转化为癌前化生细胞 转化为腺癌。胃癌的转录组学研究进展 腺癌导致了四种不同分子亚型的鉴定。这一发现有所改善 针对每种不同胃癌亚型的靶向治疗和监测策略。目前，有必要 对癌前胃上皮化生进行深入的分子分析我们最近发现， 在自身免疫环境中，化生也可以呈现不同的分子表型。这需要确定 是否由H.幽门螺杆菌感染，已知注射细胞毒素，可以干扰细胞- 可能促进致癌转化的信号通路与化生不同 由自身免疫性胃炎引起如果化生亚型是保守的，那么慢性炎症信号， 独立于病因，可能有助于癌症进展;然而，如果感染中的化生亚型 与自身免疫不同，那么细菌感染特有的因素可能会驱动另一种免疫途径， 致癌转化此外，某些炎性细胞因子（例如，IL-4/IL-13）影响 需要确定胃化生的发展和化生的特定分子亚型。 在不同的疾病背景下，识别癌前化生细胞的分子表型， 差异致癌潜力，将有助于发现新的筛选靶点，以减少胃肠道肿瘤的发生。 高易感个体的癌症负担。识别促进炎症反应的炎症信号 潜在高危化生细胞的开发将有助于发现新的治疗策略， 抑制胃癌。 在这个提议中，化生产生于两种常见的胃炎病因，H。hp感染与 自身免疫性胃炎，将分子定义和比较。人胃炎的胃上皮化生 将对患者进行转录谱分析以确定由人类疾病诱导的化生的表型。 炎性细胞因子IL-4和IL-13对诱导/扩增表型上不同亚型的 还将确定胃化生。这一工作将有助于提高对胃粘膜损伤机制的认识。 在H.幽门螺杆菌感染和自身免疫性胃炎。这些知识可以用于 改善医学预防策略并确定胃癌治疗干预的新靶点。