Mechanisms of induction of gastric injury by H. pylori

幽门螺杆菌诱导胃损伤的机制

• 批准号: 10617301
• 负责人: Elizabeth A. Marcus
• 金额: $ 39.09万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617301
• 关键词: Acceleration; Adhesions; Affect; Antibiotic Resistance; Atrophic; Bacteria; Bacterial Attachment Site; Cancer Etiology; Caring; Cell Adhesion Molecules; Cell membrane; Cell physiology; Cells; Cessation of life; Childhood; Clinical; Coculture Techniques; Critical Pathways; Data; Dependence; Development; Disease; Down-Regulation; Duodenal Ulcer; Epithelial Cells; Epithelium; Faculty; Functional disorder; Gastric Adenocarcinoma; Gastric mucosa; Gastric ulcer; Gastritis; Gastroenterologist; Gastrointestinal Diseases; Genes; Goals; Helicobacter Infections; Helicobacter pylori; Homeostasis; Impairment; In Vitro; Infection; Injections; Injury; Integration Host Factors; Ions; K ATPase; Knowledge; Malignant Neoplasms; Measures; Mediating; Membrane Potentials; Modeling; Molecular Chaperones; Mucous Membrane; Outcome; Pathology; Pathway interactions; Persons; Phosphotransferases; Physicians; Physiological; Play; Population; Post-Translational Protein Processing; Prevention; Proteins; Pump; Research; Research Proposals; Role; Scientist; Signal Induction; Signal Pathway; Signal Transduction; Sodium; Stomach; Stomach Carcinoma; System; Techniques; Treatment Protocols; Type IV Secretion System Pathway; Ulcer; Work; acute infection; advanced disease; career; chronic infection; epithelial injury; fortification; improved; in vivo; innovation; insight; malignant stomach neoplasm; mucosa-associated lymphoid tissue lymphoma; nano-string; novel; novel therapeutics; pathogen; prevent; trafficking; tumorigenesis

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.

项目概要/摘要 幽门螺杆菌是一种非常流行的病原体，世界上 50% 的人口都感染了幽门螺杆菌。 幽门螺杆菌感染至少会导致胃部炎症。 胃或十二指肠溃疡病、萎缩，或胃腺癌或MALT淋巴瘤。 全世界癌症死亡的主要原因之一，根除感染可以预防或预防癌症 由于抗生素的广泛使用，甚至胃癌的消退也变得更加困难。 尽管有许多不同的情况，但尚不清楚谁会继续发展为晚期疾病。 本研究提案的重点是研究机制。 已知与可能导致胃损伤的新宿主/细菌连接有关。 上皮损伤，初步数据表明细菌诱导 Na,K-ATP 酶下调， 它通过建立向内的钠梯度和细胞参与关键的运输功能 胃上皮细胞中 Na,K-ATP 酶活性降低导致屏障功能降低， 幽门螺杆菌对胃损伤的转运蛋白的下调针对的是新形成的泵和转运蛋白。 该机制将通过研究潜在的翻译后修饰来进一步研究。 由细菌诱导，通过观察胃泵表达减少的生理后果 细胞，并进一步表征了幽门螺杆菌泵降解机制。 从细菌的角度来看，幽门螺杆菌直接粘附在胃损伤中发挥着重要作用。 Na,K-ATP酶下调将被描述为毒力因子CagA和CagPAI的依赖性。 将确定 4 型分泌系统 (T4SS) 通过 Na,K-ATP 酶下调对胃损伤的作用。 将在肠样基质共培养模型中研究造口细胞诱导信号通路的作用。 NanoString平台将用于同时检查细菌和宿主的基因变化，以便 扩大屏障破坏和最终启动协调信号传导的研究靶点。 由细菌和宿主诱导的影响Na,K-ATP酶减少的系统将被描述，特别是 与 CagPAI T4SS 相关的途径将被探索，新的途径将通过 创新的质谱技术的完成将有助于确定幽门螺杆菌的产生原因和方式。 专门针对 Na,K-ATP 酶，识别除 CagA 之外通过 CagPAI 进入细胞的效应分子 影响 Na,K-ATP 酶水平，并描述宿主蛋白修饰的细菌因子如何诱导信号传导 级联，导致转运蛋白水平的变化这项工作的目标是获得对转运蛋白水平的新见解。 幽门螺杆菌胃损伤机制，这将带来新的治疗保护和治疗选择。