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Altering Gastric Epithelial Cell Differentiation

改变胃上皮细胞分化

基本信息

批准号：
7174208
负责人：
JUANITA L. MERCHANT
金额：
$ 27.3万
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 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7174208
关键词：
Adult Animal Model Appearance Architecture Atrophic Atrophic Gastritis Bacterial Infections Body of uterus Cell Differentiation process Cell Line Cell physiology Cells Chronic Chronic Gastritis Condition Cultured Cells Cytoplasm Development Disruption Dysplasia Ectopic Expression Enterocytes Epithelial Epithelial Cells Epithelium Erinaceidae Event Gastric Parietal Cells Gastric mucosa Gastritis Gene Targeting Genes Goals Helicobacter Infections Helicobacter pylori Human Hypochlorhydria Immune response In Vitro Inflammation Inflammatory Inflammatory Response Interferon Type II Intestinal Metaplasia Intestines Knockout Mice Lesion Lymphocyte Malignant Neoplasms Molecular Mucous Membrane Mucous body substance Mus Neoplastic Cell Transformation Organ Parietal Pattern Phenotype Population Process Proteins Pylorus Regulation Reporting Signal Pathway Signal Transduction Small Intestines Stomach Testing Thinking Time Toxin Transgenic Organisms Undifferentiated Virulence Factors bacterial resistance cell type cytokine human subject malignant stomach neoplasm mouse model neoplastic research study villin

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）：胃的慢性炎症（胃炎）通常与幽门螺杆菌有关，但也可能是由于细菌过度生长引起的。慢性胃炎也会导致壁细胞随时间的增加而减少（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，随后是胃中粘液和未分化细胞类型的扩张。有趣的是，通过异位表达毒素破坏壁细胞也被报道产生相同的表型。在某些情况下，这些表型改变进展到粘液细胞类型出现的程度，其中一个子集表达大肠杆菌特异性基因（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核心是壁细胞群的变化。在这个建议中，我们假设一个重要的触发改变正常的表型模式的胃上皮细胞是炎症产生的细菌定植。这项建议的主要目标是了解细菌感染的成分如何触发壁细胞萎缩和随后的肿瘤前变化。初步结果表明，CagA和INF（改变胃结构。首先，提出的实验使用表达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）来改变壁细胞和粘液细胞群。其次，在原代壁细胞和粘液细胞培养物中进行的体外研究将用于剖析激活的信号传导通路（目标3），并将研究在粘膜从慢性萎缩转化为发育异常期间调节的靶蛋白（目标4）。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期间丢失，并有助于粘膜增殖和随后转化的增加。这些研究将进一步加深我们对胃体萎缩如何使胃粘膜易于发生肿瘤转化的理解。