TREFOIL BINDING PROTEINS IN GASTRIC CARCINOGENESIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 胃癌是世界范围内死亡的主要原因，通常在幽门感染之前发生。 对H.幽门螺杆菌在胃癌发展中的作用为研究胃癌发生的分子和细胞事件以及发现新的胃癌生物标志物提供了新的机会。 这些见解可能导致识别胃癌风险最高的患者，并具有预后和治疗应用。 在第一个COBRE资助周期中，我们评估了H. pylori，获得R 01资金继续。 这项新的试点建议建立在我们最近对H.体内幽门螺杆菌感染。 我们使用激光捕获显微切割和基因芯片鉴定了两个新的相关基因（gastrokine [GKN] 1和2），它们在H. pylori感染的组织用于进一步研究。 我们关注GKN 1和2是因为（i）Gastrokine 2（GKN 2）是H. pylori的表达;（ii）GKN 1和GKN 2在小胃癌中的表达降低，并且我们证实在大部分胃癌病例中GKN 2的表达丢失;（iii）生物相容性-GKN 2与参与胃粘膜修复的三叶因子家族蛋白相互作用，H. pylori粘附和癌变。 我们推测：（1）GKN 1和GKN 2受H. pylori的表达，并作为胃癌的肿瘤抑制因子：（2）GKN 1和GKN 2的表达可能作为胃癌的生物标志物。 这些假设将在2年内通过以下方式进行检验：（1）检查体外和体内胃细胞中GKN 1和GKN 2变化的细胞影响，以及（2）通过评估GKN 1和GKN 2作为胃癌易感性生物标志物的实用性在一项前瞻性临床研究中H. pylori感染的患者和H.幽门诱发胃癌

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gastric cancer, a major cause of mortality worldwide, is usually preceded by pylori infection. Recognition of H. pylori's role in gastric cancer development affords novel opportunities to study the molecular and cellular events of gastric carcinogenesis and discover novel gastric cancer biomarkers. These insights may lead to the identification of patients at highest gastric cancer risk, and have prognostic and therapeutic applications. In the first COBRE funding cycle, we evaluated the mechanisms and consequences of p27 down-regulation by H. pylori, garnering R01 funding to continue. This new pilot proposal builds upon our recent analysis of the gastric epithelial cell transcriptome of H. pylori infection in vivo. We used laster capture microdissection and gene chips identified, 2 novel related genes (gastrokine [GKN] 1 and 2) that were highly significantly decreased in expression in H. pylori infected tissues were selected for further study. Our focus on GKN1 and 2 is because (i) Gastrokine 2 (GKN2) was the gene whose expression was the most down-regulated by H. pylori, (ii) decreased expression of gastrokines 1 & 2 were recently reported in small gastric cancer series by others, and confirmed by us to be lost in a large proportion of cases in gastric cancer, and (iii) biological plausibility-GKN2 interacts with trefoil factor family proteins involved in gastric mucosal repair, H. pylori adherence and carcinogenesis. We hypothesize that (1) GKN1 and GKN2 are regulated by H. pylori and act as gastric cancer tumor suppressors: and (2) expression of GKN1 and GKN2 may serve as gastric cancer biomarkers. These hypotheses will be tested over 2 years by (1) examining the cellular effects of alterations in GKN1 and GKN2 in gastric cells in vitro and in vivo and (2) by evaluating the utility of GKN1 and GKN2 as biomarkers of gastric cancer susceptibility in a prospectively clinical study of H. pylori-infected patients and in a mouse model of H. pylori-induced gastric cancer.