Oxidative Injury to Gastric Epithelial Cells by H. pylori

描述(申请人提供)：幽门螺杆菌可导致胃炎、消化性溃疡疾病、胃癌和胃淋巴瘤，然而，只有少数感染者会以溃疡或腺癌的形式发生疾病。细菌和/或宿主因素引起疾病的机制正在探索中，但确切的因素仍未完全确定。在感染期间招募到胃粘膜的吞噬细胞被激活，产生活性氧(ROS)，改变胃上皮细胞的生长并诱导细胞凋亡。此外，幽门螺杆菌感染通过产生ROS和随后激活氧化还原依赖的信号通路直接诱导胃上皮细胞氧化应激，该信号通路控制调控细胞功能的基因的转录，包括生长、修复和死亡过程。特别令人感兴趣的是ROS诱导的无嘌/脱嘧啶核酸内切酶(APE)-1，也称为氧化还原因子(Ref)-1，它可以激活转录因子，包括激活蛋白(AP)-1，核因子-kB和p53。APE-1/Ref-1在包括幽门螺杆菌感染在内的慢性炎症条件下可能是非常重要的，因为该分子可能调节受损的粘膜是修复还是容易发生肿瘤。根据迄今的研究进展，我们认为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的功能和生存。这一假说将在以下新的特定目标中得到验证：目的1.评估APE-1/Ref-1在幽门螺杆菌感染过程中胃上皮损伤中的作用。目的2.评估APE-1/Ref-1对氧化还原敏感的基因表达的转录激活作用。目的3.明确APE-1/Ref-1在基因表达负调控中的作用。这些研究将解决APE-1/Ref-1调控上皮细胞对氧化应激反应的分子机制。这些知识将提高我们对幽门螺杆菌感染相关的上皮细胞损伤的发病机制的理解，并有助于确定预防和治疗人类胃病的策略。公共卫生意义：世界上一半以上的人感染幽门螺杆菌，人们认为感染是导致大多数胃癌病例的原因，胃癌是全球第二大癌症死亡原因。因此，了解感染可能如何导致癌症的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为因素也可能是胃癌发展的关键。一些正在研究的宿主因素与炎症介质有关，但其他因素是调节对身体各种压力的反应的基因。在各种癌症的发生发展过程中，一种重要的压力就是氧化应激。我们的实验室已经证明，幽门螺杆菌感染和氧化应激都可以导致调节许多细胞功能的宿主蛋白水平上升。这种蛋白质对正常生命至关重要，因其修复细胞内受损DNA的能力而被称为无嘌呤/脱嘧啶核酸内切酶-1(简称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。我们正在开始探索APE-1/Ref-1如何影响人类胃的衬里细胞，目的是了解为什么只有一小部分幽门螺杆菌感染的患者会在这些被称为上皮的衬里细胞中出现溃疡或癌症。我们的初步结果表明，APE-1/Ref-1分子在决定这些胃衬里细胞是增殖还是生长还是死亡方面发挥了作用。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，从而影响不同的幽门螺杆菌相关疾病的发生以及发生这种疾病的机制方面发挥重要作用。

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.