Altering Gastric Epithelial Cell Differentiation

描述(申请人提供)：胃慢性炎症(胃炎)通常与幽门螺杆菌有关，但也可能是由于低盐酸导致细菌过度生长所致。慢性胃炎最初也会导致壁细胞增多，然后随着时间的推移而丧失(慢性萎缩性胃炎)。一个反复出现的主题是，壁细胞功能的破坏最终会导致壁细胞减少，随之而来的是胃中粘液和未分化细胞类型的扩张。有趣的是，据报道，通过异位表达毒素来破坏壁细胞也会产生同样的表型。在某些情况下，这些表型变化会发展到出现粘液细胞类型，其中一部分表达肠道特异基因(肠化生)。肠上皮化生是一种使胃粘膜易患癌症的疾病。启动这些重要变化的中心是壁细胞群体的变化。在这项提议中，我们假设改变胃上皮细胞正常表型模式的一个重要触发因素是细菌定植产生的炎症。这项建议的主要目标是了解细菌感染的组成部分如何引发壁细胞萎缩和随后的肿瘤前变化。初步结果表明，CagA和INF都改变了胃的结构。首先，这些实验建议使用表达CagA的转基因小鼠模型(Aim 1)或用促炎症细胞因子治疗小鼠(Aim 2)来改变壁细胞和粘液细胞群。第二，在原代壁细胞和粘液细胞培养中的体外研究，将用于剖析被激活的信号通路(目标3)，并将研究在黏膜从慢性萎缩到异型增生转变过程中调节的目标蛋白(目标4)。我们将研究主要在壁细胞中表达的Sonic hedgehog是否会在壁细胞萎缩过程中丢失，从而促进粘膜增殖和随后的转化。这些研究将进一步加深我们对胃体萎缩如何使胃粘膜发生肿瘤性转化的理解。

DESCRIPTION (provided by applicant): Chronic inflammation in the stomach (gastritis) is usually associated with Helicobacter pylori, but may occur from bacterial overgrowth because of hypochlorhydria. Chronic gastritis also results in initial increase then loss of parietal cells over time (chronic atrophic gastritis). A recurring theme is that disruption of parietal cell function eventually results in fewer parietal cells followed by an expansion of the mucous and undifferentiated cell types in the stomach. Interestingly, destruction of the parietal cell through ectopic expression of toxins has also been reported to generate the same phenotype. In some instances, these phenotypic alterations progress to the point where mucous cell types emerge, a subset of which express intestine-specific genes (intestinal metaplasia). Intestinal metaplasia is a condition that predisposes the gastric mucosa to cancer. Central to initiating these important alterations are changes in the parietal cell population. In this proposal, we hypothesize that an important trigger altering the normal phenotypic pattern of gastric epithelial cells is inflammation generated from bacterial colonization. The primary goal of this proposal is to understand how components of a bacterial infection trigger parietal cell atrophy and subsequently pre-neoplastic changes. The preliminary results show that both CagA and INF( alter gastric architecture. First, the experiments proposed use a transgenic mouse model expressing CagA (Aim 1) or treatment of mice with pro-inflammatory cytokines (Aim 2) to alter parietal and mucous cell populations. Second, in vitro studies in primary parietal and mucous cells cultures, will be used to dissect the signaling pathways activated (Aim 3) and will study the target proteins regulated during the transformation of the mucosa from chronic atrophy to dysplasia (Aim 4). We will examine whether Sonic hedgehog expressed primarily in parietal cells may be lost during parietal cell atrophy and contribute to the increase in mucosal proliferation and subsequently transformation. These studies will further our understanding of how corpus atrophy predisposes the gastric mucosa to neoplastic transformation.