GASTRIC CANCER INDUCED BY H PYLORI IN P27 DEFICIENT MICE

描述（由申请人提供）：胃癌是全球死亡率的主要原因。在大多数情况下，这种疾病是几十年的幽门螺杆菌胃感染和相关的炎症反应的结果。胃癌发生的危险因素包括特异性H.幽门螺杆菌毒力决定因子和宿主因子，如负责细胞因子和细胞因子受体表达和活性的多态性。研究的分子和细胞机制负责和根除H的可能性。幽门螺杆菌预防或减少胃癌发生的研究长期以来一直受到缺乏合适啮齿动物模型的阻碍。我们最近开发了一种新的H. p27基因缺陷小鼠幽门螺杆菌相关胃癌的实验研究结果表明：（i）H. pylori降低胃上皮细胞p27蛋白表达，（ii）p27具有肿瘤抑制蛋白的性质，和（iii）胃癌中p27的低表达与不良预后相关。用H.在60周的感染后，58%的这些小鼠发生了显著的胃发育不良或胃癌，而野生型小鼠只有7%。这些变化之前有明显的胃炎症和肠上皮化生的早期发展。我们建议测试以下假设：1。p27在骨髓源性胃炎症细胞而不是胃上皮细胞中表达的缺失是H. p27-/-小鼠的幽门螺杆菌感染。2.螺杆菌在肠上皮化生发生之前给予幽门螺杆菌根除治疗将防止H. p27-/-小鼠模型。这些假设将通过两个具体目标进行测试：1。p27-/-小鼠将在H之前接受ROSA 26野生型小鼠的骨髓移植（反之亦然）。幽门螺杆菌感染，以及骨髓移植对胃癌发展的影响将被确定。2. p27-/-小鼠感染H. pylori感染及根除H.幽门螺杆菌对胃癌发病率的影响将进行评估。干预H。在该模型中，将在频繁肠上皮化生发生之前和之后比较幽门螺杆菌根除治疗。这些研究将有助于加深对H. pylori感染，并将评估一种新的H.幽门相关胃癌的临床前试验。由于H.幽门螺杆菌被世界卫生组织列为I类（明确）致癌物，是全球癌症死亡率的第二大最常见病因，这项工作对一个重大的全球公共卫生问题具有重要意义。我们的总体长期目标是为胃癌的预防、诊断和治疗提供新的临床策略。公共卫生相关性 胃癌是世界上第二大常见的癌症死亡原因，通常是由于幽门螺杆菌感染引起的慢性胃炎引起的。研究H.幽门螺杆菌促进胃癌以及抗生素治疗是否会预防人类胃癌，由于缺乏合适的动物模型而受到阻碍。我们建议评估一种新的小鼠H.幽门螺杆菌引起的胃癌，为了解决这些重要的问题。

DESCRIPTION (provided by applicant): Gastric cancer is a major cause of worldwide mortality. In most cases, this disease is the consequence of decades of gastric infection by Helicobacter pylori and the associated inflammatory response. Risk factors for gastric cancer development include the presence of specific H. pylori virulence determinants and host factors, such as polymorphisms responsible for cytokine and cytokine receptor expression and activity. Research into both the molecular and cellular mechanisms responsible and the possibility of eradicating H. pylori to prevent or decrease gastric carcinogenesis has long been hampered by the paucity of suitable rodent models. We have recently developed a novel murine model of H. pylori-associated gastric cancer in the p27-deficient mouse, based on the following findings: (i) H. pylori decreases gastric epithelial cell p27 protein expression, (ii) p27 has the properties of a tumor suppressor protein, and (iii) low expression of p27 in gastric cancers is associated with poor prognosis. Infection of p27-deficient mice with the SS1 strain of H. pylori resulted in the development of significant gastric dysplasia or carcinoma in 58% of these mice compared with only 7% of wild- type mice after 60 weeks infection. These changes were preceded by marked gastric inflammation and the early development of intestinal metaplasia. We propose to test the following hypotheses: 1. That loss of p27 expression in bone marrow-derived gastric inflammatory cells, rather than gastric epithelial cells, is responsible for gastric carcinogenesis following H. pylori infection in p27-/- mice. 2. That H. pylori eradication therapy given prior to the development of intestinal metaplasia will prevent gastric cancer development in the H. pylori-infected p27-/- mouse model. These hypotheses will be tested by 2 specific aims: 1. p27-/- mice will receive a bone marrow transplantation from ROSA 26 wild type mice (and vice-versa) prior to H. pylori infection, and the effects of bone marrow transplantation on gastric cancer development will be determined. 2. p27-/- mice will be infected with H. pylori and the effect of eradication of H. pylori on gastric cancer incidence will be evaluated. Intervention with H. pylori eradication therapy will be compared before and after the development of frequent intestinal metaplasia in this model. These studies will lead to improved understanding of the mechanisms of gastric carcinogenesis associated with H. pylori infection and will evaluate a novel mouse model of H. pylori-associated gastric carcinogenesis for preclinical testing. Because of the designation of H. pylori by the World Health Organization as a class I (definite) carcinogen in the etiology of the second most frequent cause of worldwide cancer mortality, this work has implications for a major global public health problem. Our overall long-term goal is to contribute to the development of new clinical strategies for the prevention, diagnosis and treatment of gastric cancer.Public Health Relevance Gastric (stomach) cancer is the second most common cause of cancer death in the world, usually arising as a consequence of chronic gastritis caused by infection with Helicobacter pylori bacteria. Research to investigate how H. pylori promotes gastric cancer and whether antibiotic therapy will prevent gastric cancer in humans, has been hampered by a lack of suitable animal models. We propose to evaluate a new mouse model of H. pylori-induced gastric cancer that we have developed, in order to address these important questions.