Mechanisms of induction of gastric injury by H. pylori

项目总结/摘要 幽门螺杆菌是一种高度流行的病原体，世界上50%的人口受到感染。全是H。 幽门螺杆菌感染至少会引起胃炎。一小部分感染者最终会发展成 胃或十二指肠溃疡疾病、萎缩或胃腺癌或MALT淋巴瘤。胃癌是 它是全世界癌症死亡的主要原因之一，根除这种感染可以预防或 甚至胃癌的消退。由于抗生素的广泛使用， 阻力目前还不清楚谁会继续发展为晚期疾病，尽管有许多不同的 涉及细菌和宿主因素。这项研究提案的重点是研究机制 与可能导致胃损伤的新型宿主/细菌连接有关。H.幽门螺杆菌是已知的原因 上皮损伤，初步数据表明细菌诱导Na，K-ATP酶下调， 其通过建立内向钠梯度参与关键的转运功能，并与细胞 粘合剂。胃上皮细胞中Na，K-ATP酶活性降低导致屏障功能降低， 胃损伤H.幽门螺杆菌的目标是新形成的泵和贩运从 急诊室通过对翻译后修饰的研究，将进一步探讨其作用机制 通过观察胃粘膜上泵表达减少的生理后果， 细胞，并通过进一步表征泵降解的机制。H.幽门螺杆菌的细菌因素也发挥作用， 在诱导胃损伤中起重要作用。从细菌的角度来看，直接H.幽门粘连 将描述Na，K-ATP酶下调。对趋化因子CagA和CagPAI的依赖 4型分泌系统（T4 SS）。Na，K-ATP酶下调在胃粘膜损伤中的作用 将在肠样基质共培养模型中研究诱导来自造口细胞的信号传导途径。一 NanoString平台将用于同时检查细菌和宿主的基因变化， 扩大了屏障破坏和最终启动肿瘤发生的研究目标。协调信令 由细菌和宿主诱导的影响Na，K-ATP酶降低的系统将被描述，具体为 与CagPAI T4 SS相关;将探索已知途径，并通过以下途径鉴定新途径： 创新的质谱技术。完成这项工作将有助于确定为什么和如何H。幽门 特异性靶向Na，K-ATP酶，鉴定除了通过CagPAI进入细胞的CagA以外的效应分子 影响Na，K-ATP酶水平，并描述宿主蛋白质修饰的细菌因子如何诱导信号传导 级联，导致运输水平的变化。这项工作的目标是获得新的见解， H. pylori，这将导致新的治疗保护和治疗选择。

Project Summary/Abstract Helicobacter pylori is a highly prevalent pathogen, with 50% of the world’s population infected. All H. pylori infections at minimum cause gastric inflammation. A fraction of those infected will eventually develop gastric or duodenal ulcer disease, atrophy, or gastric adenocarcinoma or MALT lymphoma. Gastric cancer is one of the leading causes of cancer death worldwide, and eradication of the infection leads to prevention or even regression of gastric cancer. Treatment is becoming more difficult because of widespread antibiotic resistance. It is not definitively known who will go on to develop advanced disease, although many different bacterial and host factors have been implicated. The focus of this research proposal is to study mechanisms related to novel host/bacterial connections that potentially lead to gastric injury. H. pylori is known to cause epithelial injury, and preliminary data suggest that the bacteria induce downregulation of the Na,K-ATPase, which is involved with critical transport functions via establishment of an inward sodium gradient and with cell adhsion. Decreased Na,K-ATPase activity in gastric epithelial cells leads to reduced barrier function and gastric injury. Downregulation of the transporter by H. pylori targets newly formed pumps and trafficking from the ER. The mechanism will be further investigated by studying post-translational modifications potentially induced by the bacteria, by looking at the physiologic consequences of decreased pump expression on gastric cells, and by further characterizing the mechanism of pump degradation. H. pylori bacterial factors also play an important role in induction of gastric injury. From the bacterial standpoint, the role of direct H. pylori adhesion in Na,K-ATPase downregulation will be delineated. Dependence on the virulance factor CagA and the CagPAI type 4 secretion system (T4SS) will be determined. The role of gastric injury via Na,K-ATPase downregulation in induction of signaling pathways from stomal cells will be studied in an enteroid-stromal co-culture model. A NanoString platform will be used to examine gene changes in bacteria and host simultaneously in order to expand the targets studied in barrier dysruption and ultimately initiation of oncogenesis. Coordinated signaling systems induced by bacteria and host that impact decrease in Na,K-ATPase will be delineated, specifically as related to the CagPAI T4SS; known pathways will be explored and novel pathways will be identified via innovative mass spectometry techniques. Completion of this work will help determine why and how H. pylori specifically targets the Na,K-ATPase, identify effector molecules aside from CagA that enter cells via CagPAI to affect Na,K-ATPase levels, and delineate how bacterial factors modified by host proteins induce signaling cascades, leading to the changes in transporter levels. The goal of this work is to gain new insight into the mechanism of gastric injury by H. pylori, which will lead to novel therapeutic protective and treatment options.