The Role of EBI3 in Regulating Gastritis and Gastric Carcinogenesis

项目摘要：慢性炎症和化生是胃肠道疾病的先兆，包括 胃癌。尽管患有慢性炎症的人患胃癌的风险增加 胃已经知道很多年了，在我们对分子的认识上仍然存在着根本的差距 炎症影响慢性萎缩性胃炎进展的细胞过程 胃癌。对这些过程更机械化的理解可能会改进战略，以确定 那些有患胃癌风险的人，在疾病的早期阶段诊断个人，和/或开发新的 基于免疫的治疗。 细胞因子通过作用于免疫细胞来调节炎症的严重程度，从而在癌症的发生中发挥关键作用。 以及释放破坏DNA的化学物质，并通过作用于上皮细胞和调节增殖和 差异化。这与胃炎和胃癌尤其相关，因为90%的胃癌 腺癌，起源于上皮细胞，大多数发生在慢性 炎症(如幽门螺杆菌感染)。我们最近发现，使用炎症的小鼠模型- 诱导胃癌，Ebi3基因表达是减缓胃癌进展的关键 致癌。EBI3蛋白是两种细胞因子IL-27和IL-35的组成部分。这项提议的目标是 探讨EBI3(IL-27/IL-35)在胃癌发生发展中的调控作用。我们的中心假设是， 根据强有力的初步数据，IL-27和/或IL-35延缓胃炎和胃癌的进展 通过两种新的机制：1)通过调节CD4+T细胞产生细胞因子；2)调节上皮细胞 损伤和修复机制。 这项建议的具体目的是：1)确定IL-27是否通过抑制 Th17和Th22细胞；2)检测EBI3对胃上皮细胞动态平衡和/或 化生-修复；以及3)确定EBI3是由免疫细胞、上皮细胞还是同时由免疫细胞和上皮细胞表达 调节胃癌进展过程中的炎症和上皮变化。研究将在以下地点进行 来自小鼠和人的活检组织，以及小鼠和人类的胃液。拟议的研究是 创新是因为它确定了EBI3在调节免疫细胞生物学和 在胃粘膜上皮细胞，并使用创新的方法。这项拟议的研究具有重要意义 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.