Altering Gastric Epithelial Cell Differentiation

改变胃上皮细胞分化

• 批准号: 7012224
• 负责人: JUANITA L. MERCHANT
• 金额: $ 27.62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012224
• 关键词: Helicobacter; bacterial disease; bacterial proteins; biological signal transduction; cell differentiation; cell proliferation; cell transformation; cytokine; flow cytometry; gastrointestinal epithelium; genetically modified animals; immunocytochemistry; inflammation; intestinal mucosa; laboratory mouse; mass spectrometry; tissue /cell culture; yeast two hybrid system

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.

描述（由申请人提供）：胃炎（胃炎）中的慢性炎症通常与幽门螺杆菌有关，但由于多氯二硫酸毛细血管病，细菌过度生长可能发生。 慢性胃炎还会导致初始增加，然后随着时间的流逝（慢性萎缩性胃炎）的损失。 一个反复出现的主题是，顶壁细胞功能的破坏最终导致较少的顶叶细胞，然后在胃中的粘液和未分化的细胞类型扩展。 有趣的是，据报道，通过毒素的异位表达破坏顶叶细胞会产生相同的表型。 在某些情况下，这些表型改变发展到粘液细胞类型出现的点，其中的子集表达了肠道特异性基因（肠道化生）。 肠化生是一种使胃粘膜患癌症的疾病。 启动这些重要改变的核心是顶叶细胞种群的变化。 在此提案中，我们假设重要的触发因素改变了胃皮细胞的正常表型模式是由细菌定植引起的炎症。 该提案的主要目标是了解细菌感染的成分如何触发顶叶细胞萎缩，并随后进行塑性前变化。 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在粘膜从慢性萎缩转化为发育异常的过程中，我们将检查在壁细胞萎缩期间主要丢失的声音刺猬是否会丢失，而在壁细胞萎缩期间可能会丢失。