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

• 批准号: 10229463
• 负责人: Kevin A Bockerstett
• 金额: $ 4.67万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229463
• 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; In Vitro; Individual; Inflammation; Inflammatory; Lesion; Link; Malignant Neoplasms; Mediating; Metaplasia; Modeling; Molecular; Mus; Patients; Phenotype; Population; 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; gastric carcinogenesis; head-to-head comparison; human disease; immunoregulation; in vivo; interest; malignant stomach neoplasm; mouse model; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; peer; pleiotropism; premalignant; prevent; receptor; response; spasmolytic polypeptide

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.

项目摘要 胃萎缩和化生是促进胃癌发生的重要上皮细胞变化。 胃癌是一个全球性的重大公共卫生问题，是第三大癌症相关死亡原因 每年有近一百万的受害者慢性炎症是一个主要的诱发风险因素 慢性萎缩性胃炎患者的胃粘膜病变是胃癌的重要原因之一。 患癌症的风险明显高于健康的同龄人。虽然慢性病与 炎症和癌症的风险是明确的，确切的机制，炎症过程中的胃 在某些患者中导致致癌作用，但其他人则不清楚。有一个复杂的细胞因子环境 与任何慢性炎症过程相关，以及人类患者中细胞因子基因的多态性 已被证明对胃癌发展的风险有显著影响。由于强 炎症期间细胞因子产生延长与胃癌风险增加之间的关联， 我们感兴趣的是确定细胞因子在调节肿瘤发生中的机制作用， 慢性胃炎时胃萎缩和化生。 EB病毒诱导基因3（Ebi 3）编码细胞因子IL-27的蛋白亚基（EBI 3），其在细胞因子IL-27中具有良好的生物学活性。 表征并记录了炎症期间对CD 4 + T细胞的影响。EBI 3也是一种 对免疫抑制性细胞因子IL-35知之甚少，认为其由调节性T细胞（T细胞）产生。我们 使用一种新的炎症诱导胃萎缩和化生的小鼠模型TxA 23。在这个模型中，我们 发现Ebi 3产生缺陷的小鼠加速了萎缩的发展， 痉挛性多肽表达化生（SPEM），重要的癌前上皮细胞病变。我们 还观察到，作为胃炎及其引起的病变的关键抑制因子的THP， Ebi 3-/-小鼠中的缺陷型。然而，目前尚不清楚这种缺陷是否是由于外源性缺乏IL-10。 27信号传导或内在不能表达Ebi 3，从而不能表达IL-35。 我们的假设是EBI 3表达对于抑制胃炎、胃萎缩， 和胃上皮化生，部分原因是IL-27作用于THP，并增加其抑制作用。 功能协调发展的在目的1中，我们将确定IL-27是否是负责以下的关键的含EBI 3的细胞因子： 抑制疾病进展。在目标2中，我们将确定IL-27信号传导到Tcells中的作用， 胃萎缩和化生的发展。