The Role of EBI3 in Regulating Gastritis and Gastric Carcinogenesis

项目概述：慢性炎症和化生是胃肠道疾病的前兆，包括 胃癌虽然在慢性炎症患者中， 胃已经知道了很多年，但我们对分子的认识仍然存在根本性的空白。 以及炎症影响从慢性萎缩性胃炎到慢性胃炎的进展的细胞过程。 胃癌对这些过程的更机械的理解可能会改进识别 对于那些有胃癌风险的人，在疾病的早期阶段诊断个体，和/或开发新的 免疫治疗。 细胞因子通过作用于免疫细胞来调节炎症的严重程度，在癌症发生中起着关键作用 和DNA破坏化学物质的释放，并通过作用于上皮细胞和调节增殖， 分化这与胃炎和胃癌特别相关，因为>90%的胃癌 是腺癌，其来源于上皮细胞，并且大多数在慢性炎症环境中发展。 炎症（如螺杆菌感染）。我们最近发现，使用小鼠炎症模型- Ebi 3基因的表达对于减缓胃癌的进展至关重要， 致癌作用EBI 3蛋白是两种细胞因子IL-27和IL-35的组分。这项提案的目的是 确定EBI 3（IL-27/IL-35）如何调节胃癌发生的进展。我们的核心假设， 基于强有力的初步数据，IL-27和/或IL-35减缓胃炎和胃癌的进展 通过两种新的机制：1）通过调节CD 4 + T细胞的细胞因子产生，和2）调节上皮细胞 损伤和修复机制。 本提案的具体目的是：1）确定IL-27是否通过抑制炎症反应来调节胃炎的严重程度。 2）测试EBI 3对胃上皮细胞稳态和/或免疫应答的直接作用。 化生修复;以及3）确定EBI 3是否由免疫细胞、上皮细胞或这两种类型表达 调节胃癌进展过程中的炎症和上皮变化。研究将在 来自小鼠和人活组织检查中的组织，以及在小鼠和人胃腺中的组织。拟议的研究是 创新，因为它确定了EBI 3在调节免疫细胞生物学方面的新功能， 胃粘膜中的上皮细胞，并使用创新的方法。所提出的研究是有意义的 因为它有望扩大我们对细胞和分子过程的机械理解， 调节胃粘膜的炎症和化生。

Project Summary: Chronic inflammation and metaplasia are precursors to gastrointestinal diseases, including gastric cancer. Although the increased risk of gastric cancer in individuals with chronic inflammation in the stomach has been known for many years, there is still a fundamental gap in our knowledge of the molecular and cellular processes by which inflammation influences the progression from chronic atrophic gastritis to gastric cancer. A more mechanistic understanding of these processes is likely to improve strategies to identify those at risk of gastric cancer, to diagnoses individuals at an earlier stage of disease, and/or to develop new immune-based treatments. Cytokines play a critical role in carcinogenesis by acting on immune cells to regulate severity of inflammation and the release of DNA-damaging chemicals, and by acting on epithelial cells and regulating proliferation and differentiation. This is especially relevant to gastritis and gastric cancer because >90% of all gastric cancers are adenocarcinomas, which are derived from epithelial cells, and most develop in a setting of chronic inflammation (e.g. Helicobacter infection). We recently discovered, using a mouse model of inflammation- induced gastric cancer, that expression of the Ebi3 gene is critical for slowing the progression of gastric carcinogenesis. The EBI3 protein is a component of two cytokines, IL-27 and IL-35. The goal of this proposal is to identify how EBI3 (IL-27/IL-35) regulates the progression of gastric carcinogenesis. Our central hypothesis, based on strong preliminary data, is that IL-27 and/or IL-35 slow the progression of gastritis and gastric cancer by two novel mechanisms: 1) by regulating cytokine production by CD4+ T cells, and 2) regulating epithelial cell injury and repair mechanisms. The specific aims of this proposal are to: 1) Determine whether IL-27 regulates gastritis severity by inhibiting Th17 and Th22 cells; 2) Test the direct effects of EBI3 on gastric epithelial cells homeostasis and/or metaplasia-repair; and 3) Determine whether EBI3 expressed by immune cells, epithelial cells, or both types regulate inflammation and epithelial changes during gastric cancer progression. Studies will be performed in tissue from mice and in human biopsies, and in mouse and human gastroids. The proposed research is innovative because it identifies a novel functions for EBI3 in regulating the biology of immune cells and epithelial cells in the gastric mucosa and uses innovative approaches. The proposed research is significant because it is expected to expand our mechanistic understanding of the cellular and molecular processes that regulate both inflammation and metaplasia in the gastric mucosa.