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

基本信息

批准号：
8688191
负责人：
Zhibin Chen
金额：
$ 22.67万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688191
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

项目摘要

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）癌症是一种常见的致死癌。胃癌的发展被认为从胃炎，化生，发育不全到癌进行。广泛的研究已将幽门螺杆菌（HP）感染确立为胃癌的危险因素，但是HP与胃癌的关联在人群中有所不同，可能反映了与遗传和环境因素的复杂相互作用。宿主敏感性因素可能起着重要作用，但理解不太善良。独立的遗传研究将人类胃癌与CTLA4基因座的多态性相关联，该基因座预测CTLA4表达的降低。由于CTLA4在T淋巴细胞中仅表达，并且已被证明是其他类型的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，CTLA4在胃癌发生中的矛盾作用。基于CTLA4的调节缺陷可能会引发异常的炎症级联反应，从而导致胃肿瘤发生。对自发发展胃炎和肿瘤的啮齿动物模型的缺乏，对胃癌中宿主易感因素的研究受到了阻碍。我们没有使用不反映单个人类中CTLA4表达式自然变化的“全或全部”“敲除” CTLA4模型，而是创建了CTLA4 Shrna“敲低”（KD）模型来模仿CTLA4人类CTLA4 locus losus locus locus locus locuss ctla4表达的细微降低。我们发现，CTLA4调节可能会引起自发性胃粘膜化生，而不是独立于螺旋杆菌感染。我们假设在T淋巴细胞中CTLA4的表达降低会自发地通过失调的TH1和/或TH17效应子分化引起胃肿瘤发生。我们将使用遗传突变动物在TH1或TH17中阐述Th1和Th17在CTLA4调制引起的胃中植物中的作用来检验这一假设。这项研究旨在提供有关适应性免疫的主抑制剂如何抑制肿瘤发生的新知识的新颖和深入的知识，其长期目标是确定预防胃癌的策略。