Role of Th1/17 in gastric tumor initiation triggered by CTLA4 dysregulation

Th1/17 在 CTLA4 失调引发的胃肿瘤发生中的作用

• 批准号: 8570484
• 负责人: Zhibin Chen
• 金额: $ 13.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570484
• 关键词: Acute; Adverse effects; Affect; Animal Model; Animals; Antibodies; Biological; Blocking Antibodies; Cancer Patient; Carcinoma; Cells; Child; Clinical; Clinical Treatment; Clinical Trials; Complex; Conflict (Psychology); Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Defect; Development; Dysplasia; Effector Cell; Elderly; Environmental Risk Factor; Exons; Gastric Adenocarcinoma; Gastric Metaplasia; Gastric mucosa; Gastritis; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Helicobacter Infections; Helicobacter pylori; Human; Immune; Immunity; Immunotherapy; Individual; Infection; Inflammation; Inflammatory; Interferons; Interleukin-17; Knock-out; Knowledge; Lead; Literature; Long-Term Effects; Malignant Neoplasms; Mediating; Metaplasia; Metaplastic; Modeling; Monitor; Mus; Pathology; Penetrance; Play; Population; Predisposition; Regulation; Risk Factors; Rodent Model; Role; Stomach; Stomach Neoplasms; T-Lymphocyte; Testing; Th1 Cells; Tumor Immunity; Variant; adaptive immunity; base; cancer immunotherapy; cancer type; carcinogenesis; cytokine; gastric cancer prevention; gastrointestinal; inhibitor/antagonist; juvenile animal; malignant stomach neoplasm; mutant; novel; patient population; prevent; promoter; public health relevance; receptor expression; research study; response; risk benefit ratio; small hairpin RNA; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): Stomach (gastric) cancer is a common lethal cancer. Development of gastric cancer is thought to proceed from gastric inflammation, metaplasia, dysplasia to carcinoma. Extensive studies have established Helicobacter pylori (HP) infection as a risk factor for gastric cancer, but the association of HP with gastric cancers varies in populations, likely reflecting a complex interaction with genetic and environmental factors. Host susceptibility factors may play an important role but are less well-understood. Independent genetic studies have associated human gastric cancer with polymorphisms of the CTLA4 locus that predict a reduction in CTLA4 expression. Since CTLA4 is exclusively expressed in T lymphocytes and has been demonstrated as a prototypical inhibitor of anti-tumor immunity in other types of cancers, observations from the genetic study suggest a paradoxical role of CTLA4 in gastric carcinogenesis. Defect in CTLA4-based regulation could trigger an aberrant inflammatory cascade that lead to gastric tumorigenesis. The study of the host susceptibility factors in gastric cancer has been hindered by a dearth of rodent models that spontaneously develop gastric inflammation and tumors. Rather than using the "all-or-nothing" "knockout" CTLA4 models that do not reflect natural variations of CTLA4 expressions among individual humans, we have created CTLA4 shRNA "knockdown" (KD) models to mimic the subtle reductions of CTLA4 expression predicted by polymorphisms of human CTLA4 locus. We found that CTLA4 modulation could cause spontaneous gastric mucosal metaplasia independently of Helicobacter infection. We hypothesize that Reduced Expression of a CTLA4 in T Lymphocytes Spontaneously Initiates Gastric Tumorigenesis through Dysregulated Th1 and/or Th17 Effector Differentiation. We will test this hypothesis by dissecting the roles of Th1 and Th17 in gastric metaplasia induced by CTLA4 modulation, using genetic mutant animals deficient in Th1 or Th17. This study aims to provide novel and in-depth knowledge on how a master inhibitor of adaptive immunity suppresses initiation of tumorigenesis, with a long-term goal to identify strategies for gastric cancer prevention.

描述（由申请人提供）：胃（胃）癌是一种常见的致死性癌症。胃癌的发生发展被认为是从胃粘膜炎症、化生、异型增生到癌变的过程。广泛的研究已经确定幽门螺杆菌（HP）感染是胃癌的危险因素，但HP与胃癌的相关性在人群中各不相同，可能反映了与遗传和环境因素的复杂相互作用。宿主易感性因素可能发挥重要作用，但不太清楚。独立的遗传学研究已经将人类胃癌与CTLA 4基因座的多态性相关联，所述多态性预测CTLA 4表达的减少。由于CTLA 4仅在T淋巴细胞中表达，并且已被证明是其他类型癌症中抗肿瘤免疫的原型抑制剂，因此遗传研究的观察结果表明CTLA 4在胃癌发生中的矛盾作用。CTLA 4调控的缺陷可能引发异常的炎症级联反应，导致胃肿瘤的发生。由于缺乏自发性发生胃炎症和肿瘤的啮齿动物模型，对胃癌宿主易感因素的研究受到阻碍。不是使用不反映个体人类中CTLA 4表达的自然变化的“全有或全无”“敲除”CTLA 4模型，我们已经创建了CTLA 4 shRNA“敲低”（KD）模型来模拟由人类CTLA 4基因座的多态性预测的CTLA 4表达的细微降低。我们发现CTLA 4调节可以独立于螺杆菌感染而引起自发性胃粘膜化生。我们推测，CTLA 4在T淋巴细胞中自发表达减少通过Th 1和/或Th 17效应分化失调启动胃癌发生。我们将使用Th 1或Th 17缺陷的遗传突变动物，通过解剖Th 1和Th 17在CTLA 4调制诱导的胃上皮化生中的作用来验证这一假设。本研究旨在提供关于获得性免疫的主要抑制剂如何抑制肿瘤发生的新的和深入的知识，其长期目标是确定胃癌预防的策略。