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）：幽门螺杆菌引起胃炎、消化性溃疡病、胃癌和胃淋巴瘤，然而，只有一小部分感染者会发展为溃疡或腺癌形式的疾病。细菌和/或宿主因素引起疾病的机制正在探索，但确切的因素仍未完全确定。感染期间招募到胃粘膜的吞噬白细胞被激活，产生活性氧（ROS），改变胃上皮细胞生长并诱导细胞凋亡。此外，幽门螺杆菌感染通过产生ROS并随后激活氧化还原依赖性信号通路，直接在胃上皮细胞中诱导氧化应激，该信号通路控制调节细胞功能（包括生长、修复和死亡过程）的基因转录。特别令人感兴趣的是 ROS 诱导的无嘌呤/无嘧啶核酸内切酶 (APE)-1（也称为氧化还原因子 (Ref)-1）的激活，它可以激活转录因子，包括激活蛋白 (AP)-1、NF-kB 和第 53 页。 APE-1/Ref-1 在慢性炎症性疾病（包括幽门螺杆菌感染）中可能非常重要，因为该分子可以调节受损粘膜是否得到修复或容易发生肿瘤。根据迄今为止的进展，我们提出幽门螺杆菌感染通过 APE-1/Ref-1 刺激氧化还原敏感信号，从而调节胃上皮细胞功能和存活。该假设将在以下新的具体目标中得到检验： 目标 1. 评估 APE-1/Ref-1 在幽门螺杆菌感染期间胃上皮损伤中的作用。目标 2. 评估 APE-1/Ref-1 对基因表达的氧化还原敏感转录激活。目标 3. 明确 APE-1/Ref-1 在基因表达负调控中的作用。这些研究将探讨 APE-1/Ref-1 控制上皮细胞对氧化应激反应的分子机制。这些知识将提高我们对幽门螺杆菌感染相关上皮细胞损伤发病机制的理解，并有助于确定预防和治疗人类胃病的策略。公共卫生相关性：公共卫生意义 世界上一半以上的人感染幽门螺杆菌，人们认为感染导致大多数胃癌病例，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生的关键。正在研究的一些宿主因素与炎症介质有关，但其他因素是调节身体对各种压力的反应的基因。在各种癌症的发展中重要的一种压力是氧化应激。我们的实验室表明，幽门螺杆菌感染和氧化应激都会导致调节许多细胞功能的宿主蛋白水平升高。这种蛋白质对于正常生命至关重要，因其能够修复细胞中受损的 DNA 而被称为无嘌呤/无嘧啶核酸内切酶-1（简称 APE -1）。该分子的另一个特性（也称为氧化还原因子 -1 (Ref-1)）是调节所有哺乳动物细胞内的生化机制的功能。我们开始探索 APE-1/Ref-1 如何影响人类胃壁细胞，目的是了解为什么只有一部分幽门螺杆菌感染患者会在这些被称为胃壁细胞的壁细胞中出现溃疡或癌症。上皮。我们的初步结果表明，APE-1/Ref-1 分子在确定这些胃壁细胞是否增殖或生长或是否死亡方面发挥着作用。细胞生长或死亡的平衡被认为是了解癌症和其他胃病如何发展的关键领域。拟议的工作将在确定 APE-1/Ref-1 如何调节宿主对感染的反应并从而影响不同的幽门螺杆菌相关疾病的发生及其可能发生的机制方面发挥重要作用。