Altering Gastric Epithelial Cell Differentiation

改变胃上皮细胞分化

基本信息

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
项目类别：
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

项目摘要

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）：胃部慢性炎症（胃炎）通常与幽门螺杆菌有关，但也可能是由于胃酸过少导致细菌过度生长而引起的。慢性胃炎还会导致壁细胞随着时间的推移最初增加然后减少（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，随后胃中粘液和未分化细胞类型扩张。有趣的是，据报道，通过毒素的异位表达破坏壁细胞也会产生相同的表型。在某些情况下，这些表型改变会发展到出现粘液细胞类型的程度，其中一部分表达肠道特异性基因（肠化生）。肠化生是一种使胃粘膜易患癌症的疾病。启动这些重要改变的核心是壁细胞群的变化。在这个提议中，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。该提案的主要目标是了解细菌感染的成分如何引发壁细胞萎缩以及随后的肿瘤前变化。初步结果表明，CagA 和 INF( 都会改变胃结构。首先，实验建议使用表达 CagA 的转基因小鼠模型（目标 1）或用促炎细胞因子治疗小鼠（目标 2）来改变壁细胞和粘液细胞群其次，原代壁细胞和粘液细胞培养物的体外研究将用于剖析激活的信号通路（目标 3），并研究粘膜转化过程中受调节的靶蛋白。我们将研究主要在壁细胞中表达的 Sonic Hedgehog 是否可能在壁细胞萎缩过程中丢失，并有助于粘膜增殖和随后的转化的增加。胃粘膜向肿瘤转化。