Regulation of Gastric Epithelial Cells in the Mouse

小鼠胃上皮细胞的调节

• 批准号: 7344824
• 负责人: LINDA C. SAMUELSON
• 金额: $ 29.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7344824
• 关键词: Acids; Age; Antibodies; Apoptosis; Apoptotic; Atrophic; Atrophic Gastritis; Autoantibodies; Autoimmune Diseases; Autoimmunity; Bioinformatics; CD4 Positive T Lymphocytes; Cell Death; Cell physiology; Cessation of life; Cholera Toxin A Subunit; Chronic; Chronic Gastritis; Cyclic AMP; Data; Dependency; Development; Down-Regulation; Epithelial Cells; Exhibits; Experimental Models; Functional disorder; Funding; Gastric Parietal Cells; Gastric mucosa; Gastrins; Gastritis; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Germ-Free; H(+)-K(+)-Exchanging ATPase; Health; Helicobacter; Helicobacter Infections; Human; Immune response; Immune system; In Situ Nick-End Labeling; Inbred BALB C Mice; Inflammation; Inflammatory Infiltrate; Inflammatory Response; Interferons; Lead; Leucocytic infiltrate; Measures; Modeling; Morphology; Mus; Neonatal; Pathology; Pernicious Anemia; Production; Proteins; Regulation; Research Personnel; Role; Signal Transduction; Staining method; Stains; Stomach; Stomach Carcinoma; Testing; Thymectomy; Transgenic Mice; Transgenic Organisms; autoimmune gastritis; cytokine; insight; malignant stomach neoplasm; mouse model; novel strategies; pathogen; programs; promoter; research study; response; transgene expression; tumor

DESCRIPTION (provided by applicant): This is an A2 application that uses genetically engineered mice to evaluate the regulation of parietal cell function and mechanisms involved in the development of autoimmune gastritis (AIG). The analysis is focused on the Ctox7 transgenic mouse model, which was developed in the previous funding period. Ctox transgenics have enhanced acid secretion resulting from increased parietal cell cAMP. As the mice age they develop atrophic gastritis associated with the production of anti-parietal cell antibodies. The spontaneous development of autoimmunity defines a new experimental model for AIG, which is the focus of this application. We test the following overriding hypothesis: Hyperstimulation of the parietal cell due to chronic high cAMP leads to inflammation, which results in the development of AIG and the destruction of parietal cells and eventual gastric mucosal transformation. Three specific aims are directed to different aspects of the proposed mechanism. Aim 1 will focus on the significance of the cAMP hyperstimulation in regard to parietal cell function and death. Our preliminary results show increased TUNEL staining in the glandular compartment suggesting an apoptotic mechanism for the atrophy. We will test whether increased parietal cell cAMP predisposes the parietal cell to sensitivity to cytokine-induced cell death. We will also examine changes in morphology and gene expression resulting from increased cAMP to further understand the significance of this critical parietal cell signaling regulator. Aim 2 will focus on the inflammatory response and test the hypothesis that AIG is associated with a Th1 immune response dependent on the cytokine interferon-7 (IFN-y). Cellular infiltrates will be characterized by FACS analysis and cytokine production in stomach and spenocytes will be analyzed. Preliminary data shows Ctox7 transgenics have increased IFN-y expression. Analyzing Ctox7 transgenics on an IFN-y deficient background will test cytokine dependency. Aim 3 will test the strain-dependency of AIG and whether inflammation induced by environmental pathogens can enhance the development of AIG. Spontaneous development of autoimmunity in a C57BL/6 strain is unique to the Ctox7 model of autoimmune gastritis. We will also test Ctox7 on a Balb/c background, which is the permissive strain background for other models of AIG. This aim will also examine the importance of environmental pathogens by analysis of Helicobacter infected and germ-free mice. These experiments will compare the Ctox7 model to the previously characterized mouse thymectomy model of AIG. Chronic atrophic gastritis, and AIG leading to pernicious anemia are significant human health concerns. This project will use a new experimental mouse model of AIG to examine mechanisms leading to the development of autoimmune disease in the stomach. These studies will further our understanding of the significance of parietal cell stimulation and Helicobacter infection on the development of gastric inflammation, which is associated with the development of stomach cancer.

描述（由申请人提供）：这是一项A2申请，使用基因工程小鼠评价壁细胞功能的调节和自身免疫性胃炎（AIG）发生的机制。分析的重点是在前一个资助期开发的Ctox 7转基因小鼠模型。Ctox转基因具有由增加的壁细胞cAMP引起的增强的酸分泌。随着小鼠年龄的增长，它们发展为与抗壁细胞抗体的产生相关的萎缩性胃炎。自身免疫的自发发展为AIG定义了一个新的实验模型，这是本申请的重点。我们测试了以下压倒一切的假设：由于慢性高cAMP过度刺激壁细胞导致炎症，这导致AIG的发展和壁细胞的破坏，并最终胃粘膜转化。拟议机制的不同方面有三个具体目标。目的1将集中在环腺苷酸过度刺激壁细胞功能和死亡方面的意义。我们的初步结果表明，增加TUNEL染色腺室表明细胞凋亡机制的萎缩。我们将测试壁细胞cAMP的增加是否使壁细胞对苦参碱诱导的细胞死亡敏感。我们还将研究由cAMP增加引起的形态学和基因表达的变化，以进一步了解这种关键的壁细胞信号调节剂的意义。目的2将集中在炎症反应和测试的假设，AIG与Th 1免疫反应依赖于细胞因子干扰素-7（IFN-γ）。将通过FACS分析表征细胞浸润，并将分析胃和脾细胞中的细胞因子产生。初步数据显示Ctox 7转基因增加了IFN-γ表达。在IFN-γ缺陷背景下分析Ctox 7转基因将测试细胞因子依赖性。目的3将测试AIG的菌株依赖性以及环境病原体诱导的炎症是否可以促进AIG的发展。C57 BL/6菌株中自身免疫的自发发展是自身免疫性胃炎的Ctox 7模型所独有的。我们还将在Balb/c背景下测试Ctox 7，这是AIG其他模型的许可菌株背景。这一目标还将通过分析螺杆菌感染和无菌小鼠来研究环境病原体的重要性。这些实验将比较Ctox 7模型与先前表征的AIG小鼠胸腺切除模型。慢性萎缩性胃炎和导致恶性贫血的AIG是重要的人类健康问题。该项目将使用一种新的AIG实验小鼠模型来研究导致胃部自身免疫性疾病发展的机制。这些研究将进一步加深我们对壁细胞刺激和螺杆菌感染在胃炎症发展中的意义的理解，而胃炎症与胃癌的发生有关。