Oxidative Injury to Gastric Epithelial Cells by H. pylori

幽门螺杆菌对胃上皮细胞的氧化损伤

• 批准号: 7637368
• 负责人: Sheila E. Crowe
• 金额: $ 32.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-21 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637368
• 关键词: Address; Adenocarcinoma; Affect; Amino Acids; Apoptosis; Area; Bacteria; Base Excision Repairs; Binding; Biochemical; Biological; Biological Assay; Calcium; Cancer Etiology; Cell Cycle; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Cysteine; DNA Binding; DNA Repair; Data; Development; Disease; Enzymes; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Event; Family; Funding; GADD45; Gastric lymphoma; Gastric mucosa; Gastritis; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Goals; Growth; Helicobacter Infections; Helicobacter pylori; Human; Human Cell Line; Hypoxia Inducible Factor; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Integration Host Factors; Interleukin-8; Interphase Cell; Knowledge; Laboratories; Lead; Lesion; Leukocytes; Life; Lymphoma; Malignant Neoplasms; Mammalian Cell; Measurement; Messenger RNA; Molecular; Mucous Membrane; NF-kappa B; Neoplasms; Nuclear Translocation; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peptic Ulcer; Phagocytes; Play; Prevention strategy; Process; Proliferating; Promoter Regions; Property; Proteins; Public Health; Pylorus; Reactive Oxygen Species; Recruitment Activity; Reporter; Research; Response Elements; Role; Signal Pathway; Signal Transduction; Stomach; Stomach Carcinoma; Stomach Diseases; Stress; TP53 gene; Testing; Transcription Factor AP-1; Transcriptional Activation; Translating; Ulcer; Work; activating transcription factor; base; cell growth; cell injury; chemokine; cytokine; endonuclease; gene function; human tissue; improved; in vivo; interest; malignant stomach neoplasm; member; protein expression; public health relevance; repaired; response; transcription factor

DESCRIPTION (provided by applicant): Helicobacter pylori causes gastritis, peptic ulcer disease, gastric carcinoma, and gastric lymphoma, however, only a subset of infected individuals develops disease in the form of ulceration or adenocarcinoma. The mechanisms by which bacterial and/or host factors cause disease are being explored, but exact factors remain incompletely defined. Phagocytic leukocytes recruited to the gastric mucosa during infection become activated, generating reactive oxygen species (ROS) that alter gastric epithelial cell growth and induce apoptosis. In addition, H. pylori infection induces oxidative stress directly in gastric epithelial cells through the generation of ROS and the subsequent activation of a redox-dependent signaling pathway which controls the transcription of genes that regulate cell function, including growth, repair, and death processes. Of particular interest is ROS- induced activation of apurinic/apyrimidinic endonuclease (APE)-1, also known as redox factor (Ref)-1, that can activate transcription factors, including activator protein (AP)-1, NF-kB, and p53. APE-1/Ref-1 is potentially very important in chronic inflammatory conditions, including H. pylori infection, since this molecule may regulate whether damaged mucosa is repaired or vulnerable to the development of neoplasia. Based on progress to date, we propose that H. pylori infection stimulates redox-sensitive signaling through APE-1/Ref-1 that regulates gastric epithelial cell function and survival. This hypothesis will be examined in the following new specific aims: Aim 1. Evaluate role of APE-1/Ref-1 in gastric epithelial injury during H. pylori infection. Aim 2. Assess redox-sensitive transcriptional activation of gene expression by APE-1/Ref-1. Aim 3. Define the role of APE-1/Ref-1 in negative regulation of gene expression. These studies will address the molecular mechanisms whereby APE-1/Ref-1 governs epithelial responses to oxidative stress. This knowledge will improve our understanding of the pathogenesis of epithelial cell damage associated with H. pylori infection and help identify strategies for the prevention and treatment of human gastric disease. PUBLIC HEALTH RELEVANCE: Public Health Significance Over half the world is infected with Helicobacter pylori and it is thought that infection contributes to most cases of gastric cancer, the second most common cause of cancer death worldwide. Thus, understanding how infection may lead to cancer development is an important area for research. It is also apparent that individual human factors known as host factors may also be key in the development of gastric cancer. Some of the host factors being studied relate to inflammatory mediators but other factors are genes that regulate the response to various stresses to the body. One such stress that is important in the development of various cancers is something known as oxidative stress. Our laboratory has shown that H. pylori infection and oxidative stress can each lead to increased levels of a host protein that regulates many cell functions. This protein is vital for normal life and is known as apurinic/apyrimidinic endonuclease-1 (APE -1 for short) for its ability to repair damaged DNA in cells. Another property of this molecule also known as Redox factor -1 (Ref-1) is to regulate how the biochemical machinery within all mammalian cells functions. We are starting to explore how APE- 1/Ref-1 affects the cells that line the human stomach with the goal of understanding why only a subset of patients with H. pylori infection will get ulcers or cancer arising in these lining cells known as the epithelium. Our initial results show that the APE-1/Ref-1 molecule plays a role in determining whether these stomach lining cells proliferate or grow or whether they die. The balance in growth or death of cells is felt to be a key area in understanding how cancers and other gastric diseases develop. The proposed work will play an important role in role in establishing how APE-1/Ref-1 may modulate host responses to infection and consequently influence in whom different H. pylori-associated diseases arise and the mechanisms by which this may happen.

描述（由申请人提供）：幽门螺杆菌可引起胃炎、消化性溃疡、胃癌和胃淋巴瘤，然而，只有一部分感染个体会发生溃疡或腺癌。细菌和/或宿主因素引起疾病的机制正在探索中，但确切的因素仍不完全确定。在感染期间被募集到胃粘膜的吞噬性白细胞被激活，产生改变胃上皮细胞生长并诱导凋亡的活性氧（ROS）。此外，H.幽门螺杆菌感染通过ROS的产生和随后的氧化还原依赖性信号通路的激活直接在胃上皮细胞中诱导氧化应激，所述氧化还原依赖性信号通路控制调节细胞功能（包括生长、修复和死亡过程）的基因的转录。特别感兴趣的是ROS诱导的脱嘌呤/脱嘧啶核酸内切酶（APE）-1（也称为氧化还原因子（Ref）-1）的活化，其可以活化转录因子，包括活化蛋白（AP）-1、NF-κ B和p53。APE-1/Ref-1在慢性炎症性疾病中可能非常重要，包括H. pylori感染，因为这种分子可以调节受损的粘膜是否被修复或易受肿瘤形成的影响。根据迄今为止的进展，我们建议H。幽门螺杆菌感染通过APE-1/Ref-1刺激氧化还原敏感性信号传导，调节胃上皮细胞功能和存活。这一假设将在以下新的具体目标中加以审查：目标1。APE-1/Ref-1在H.幽门感染目标2.评估APE-1/Ref-1对基因表达的氧化还原敏感性转录激活。目标3。定义APE-1/Ref-1在基因表达负调控中的作用。这些研究将阐明APE-1/Ref-1调控上皮细胞对氧化应激反应的分子机制。这些知识将有助于我们更好地理解与H.幽门螺杆菌感染，并帮助确定预防和治疗人类胃病的策略。公共卫生关系：世界上一半以上的人感染了幽门螺杆菌，据认为，感染导致了大多数胃癌病例，胃癌是全球癌症死亡的第二大常见原因。因此，了解感染如何导致癌症发展是一个重要的研究领域。同样明显的是，被称为宿主因素的个体人类因素也可能是胃癌发展的关键。正在研究的一些宿主因子与炎症介质有关，但其他因子是调节对身体各种应激反应的基因。其中一种在各种癌症发展中很重要的压力是被称为氧化应激的东西。实验室研究表明，H.幽门螺杆菌感染和氧化应激可各自导致调节许多细胞功能的宿主蛋白质的水平增加。这种蛋白质对正常生活至关重要，因其修复细胞中受损DNA的能力而被称为脱嘌呤/脱嘧啶核酸内切酶-1（APE-1）。这种分子的另一个特性也被称为氧化还原因子-1（Ref-1），是调节所有哺乳动物细胞内的生化机制如何发挥作用。我们开始探索APE- 1/Ref-1如何影响人类胃细胞，目的是了解为什么只有一部分H。幽门螺杆菌感染会导致溃疡或癌症，这些衬里细胞称为上皮细胞。我们的初步结果表明，APE-1/Ref-1分子在决定这些胃粘膜细胞是否增殖或生长或是否死亡方面发挥作用。细胞生长或死亡的平衡被认为是理解癌症和其他胃病如何发展的关键领域。这项工作将在确定APE-1/Ref-1如何调节宿主对感染的反应，从而影响不同的H.幽门相关疾病的出现以及可能发生的机制。