Altering Gastric Epithelial Cell Differentiation

改变胃上皮细胞分化

• 批准号: 6577518
• 负责人: JUANITA L. MERCHANT
• 金额: $ 28.21万
• 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/6577518
• 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）：胃慢性炎症（胃炎）通常与幽门螺杆菌有关，但也可能由低氯酸引起的细菌过度生长引起。慢性胃炎也会导致壁细胞的增加，然后随着时间的推移而减少（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导致壁细胞减少，随后是胃粘膜和未分化细胞类型的扩大。有趣的是，据报道，通过毒素的异位表达破坏顶壁细胞也会产生相同的表型。在某些情况下，这些表型改变进展到出现粘液细胞类型，其中一部分表达肠道特异性基因（肠化生）。肠化生是一种易使胃粘膜癌变的疾病。启动这些重要改变的核心是壁细胞群的变化。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。本建议的主要目的是了解细菌感染的成分如何引发顶壁细胞萎缩和随后的肿瘤前变化。初步结果表明，CagA和INF（）均可改变胃结构。首先，实验建议使用表达CagA的转基因小鼠模型（Aim 1）或用促炎细胞因子治疗小鼠（Aim 2）来改变顶壁和粘膜细胞群。其次，在原代壁细胞和粘膜细胞培养的体外研究中，将用于解剖激活的信号通路（Aim 3），并将研究在粘膜从慢性萎缩到发育不良的转化过程中调节的靶蛋白（Aim 4）。我们将研究主要在壁细胞中表达的Sonic hedgehog基因是否会在壁细胞萎缩期间丢失，并导致粘膜增殖和随后的转化增加。这些研究将进一步加深我们对胃萎缩如何使胃粘膜易发生肿瘤转化的理解。