The Role of Epstein-Barr Virus-Induced Gene 3 (EBI3) in Preventing Gastric Atrophy and Metaplasia

EB 病毒诱导基因 3 (EBI3) 在预防胃萎缩和化生中的作用

基本信息

批准号：
9768884
负责人：
Kevin A Bockerstett
金额：
$ 3万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768884
关键词：
Adenocarcinoma Adoptive Cell Transfers Affect Atrophic Atrophic Gastritis Biological Assay CD4 Positive T Lymphocytes Cancer Etiology Cancer Patient Categories Cause of Death Cells Cessation of life Chronic Chronic Gastritis Complex Cytokine Gene Data Defect Development Disease Disease Progression Epithelial Cells Epstein-Barr Virus Infections Etiology Exhibits FOXP3 gene Gastric Metaplasia Gastric Parietal Cells Gastritis Genes Genetic Polymorphism Goals Helicobacter Infections High-Risk Cancer Human Human Herpesvirus 4 Immune Immune system Immunosuppressive Agents In Vitro Individual Inflammation Inflammatory Lesion Link Malignant Neoplasms Mediating Metaplasia Modeling Molecular Mus Patients Phenotype Population Premalignant Process Production Protein Subunits Public Health Regulatory T-Lymphocyte Research Risk Risk Factors Role Signal Transduction Signaling Molecule Stomach Stomach Diseases Surface T-Lymphocyte Testing Tissues autoimmune gastritis cancer risk carcinogenesis congenic cytokine experimental study expression vector head-to-head comparison human disease immunoregulation in vivo interest malignant stomach neoplasm mouse model novel novel diagnostics novel therapeutics peer pleiotropism prevent receptor response spasmolytic polypeptide

项目摘要

PROJECT SUMMARY Gastric atrophy and metaplasia are critical epithelial cell changes that promote gastric carcinogenesis. Gastric cancer is a major public health issue world-wide, being the third leading cause of cancer-related death in the world with nearly one million victims every year. Chronic inflammation is a major predisposing risk factor for the development of gastric cancer, demonstrated by the fact that patients with chronic atrophic gastritis have significantly higher risk of cancer than their healthy peers. While the association between chronic inflammation and cancer risk is clear, the exact mechanisms by which the inflammatory process in the stomach leads to carcinogenesis in some patients but not others are not understood. There is a complex cytokine milieu associated with any chronic inflammatory process, and polymorphisms in cytokine genes in human patients have been shown to have a significant effect on the risk of gastric cancer development. Due to the strong association between the prolonged cytokine production during inflammation and increased gastric cancer risk, we are interested in determining the mechanistic role that cytokines serve in regulating the development of gastric atrophy and metaplasia during chronic gastritis. Epstein-Barr Virus-Induced Gene 3 (Ebi3) encodes a protein subunit (EBI3) of the cytokine IL-27, which is well- characterized and has documented effects on CD4+ T cells during inflammation. EBI3 is also a component of the poorly understood immunosuppressive cytokine IL-35 thought to be made by regulatory T cells (Tregs). We use a novel murine model of inflammation-induced gastric atrophy and metaplasia, TxA23. In this model we have discovered that mice deficient in the production of Ebi3 have accelerated development of atrophy and spasmolytic polypeptide expressing metaplasia (SPEM), important preneoplastic epithelial cell lesions. We have also observed that Tregs, which are critical suppressors of gastritis and resulting lesions, exhibit a defective phenotype in Ebi3-/- mice. However, it is unclear whether this defect is due to the extrinsic lack of IL- 27 signaling or the intrinsic inability to express Ebi3, and thereby IL-35. Our hypothesis is that EBI3 expression is critical for suppressing the development of gastritis, gastric atrophy, and gastric metaplasia due in part to the effects of IL-27 acting on Tregs and increasing their suppressive functions. In Aim 1 we will determine whether IL-27 is the critical EBI3 containing cytokine responsible for suppressing disease progression. In Aim 2, we will determine the effect of IL-27 signaling into Tregs during the development of gastric atrophy and metaplasia.

项目概要胃萎缩和化生是促进胃癌发生的关键上皮细胞变化。胃癌是世界范围内的一个重大公共卫生问题，是癌症相关死亡的第三大原因世界上每年有近百万受害者。慢性炎症是主要的诱发危险因素慢性萎缩性胃炎患者的事实证明，患癌症的风险明显高于健康同龄人。虽然慢性病之间的关联炎症和癌症风险是明确的，胃部炎症过程的确切机制导致某些患者致癌，但尚不清楚其他患者是否会致癌。存在复杂的细胞因子环境与任何慢性炎症过程以及人类患者细胞因子基因多态性相关已被证明对胃癌发生的风险有显着影响。由于强炎症期间细胞因子长时间产生与胃癌风险增加之间的关联，我们有兴趣确定细胞因子在调节细胞发育中的机制作用慢性胃炎时胃萎缩和化生。 Epstein-Barr 病毒诱导基因 3 (Ebi3) 编码细胞因子 IL-27 的蛋白质亚基 (EBI3)，该亚基很好地表征并记录了炎症期间对 CD4+ T 细胞的影响。 EBI3 也是人们对免疫抑制细胞因子 IL-35 知之甚少，人们认为它是由调节性 T 细胞 (Treg) 产生的。我们使用炎症诱导的胃萎缩和化生的新型小鼠模型 TxA23。在这个模型中我们发现缺乏 Ebi3 产生的小鼠会加速萎缩的发展解痉多肽表达化生（SPEM），重要的肿瘤前上皮细胞病变。我们还观察到 Tregs 是胃炎及其引起的病变的关键抑制因子，表现出 Ebi3-/- 小鼠的缺陷表型。然而，尚不清楚这种缺陷是否是由于外源性缺乏IL- 27 信号传导或内在无法表达 Ebi3，从而无法表达 IL-35。我们的假设是 EBI3 表达对于抑制胃炎、胃萎缩、和胃化生的部分原因是 IL-27 作用于 Tregs 并增加了其抑制作用功能。在目标 1 中，我们将确定 IL-27 是否是负责 EBI3 的关键细胞因子抑制疾病进展。在目标 2 中，我们将确定 IL-27 信号传导对 Tregs 的影响胃萎缩和化生的发展。