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.

项目摘要/摘要 幽门螺杆菌是一种高度普遍的病原体，其中50％的人口感染。所有H. 最小的幽门螺杆菌感染引起胃感染。一小部分被感染的人最终会发展 胃或十二指肠溃疡疾病，萎缩或胃腺癌或麦芽淋巴瘤。胃癌是 全球癌症死亡的主要原因之一，根除感染导致预防或 甚至胃癌的消退。由于宽度抗生素，治疗变得越来越困难 反抗。尚不清楚谁将继续发展晚期疾病，尽管许多不同 已经暗示了细菌和宿主因素。该研究建议的重点是研究机制 与可能导致胃损伤的新型宿主/细菌连接有关。已知幽门螺杆菌引起 上皮损伤和初步数据表明，细菌会诱导Na，K-ATPase的下调， 通过建立向内钠梯度和细胞，它与关键的运输功能有关 Adhsion。胃皮细胞中Na，K-ATPase活性的降低导致屏障功能降低和 胃损伤。幽门螺杆菌对转运蛋白的下调，靶向新形成的泵和贩运 急诊室。通过研究翻译后修饰，将进一步研究该机制 通过细菌诱导的，通过查看降低泵表达对胃的生理后果 细胞，并进一步表征泵降解的机理。幽门螺杆菌的概况也可以 胃损伤的重要作用。从细菌的角度来看，幽门螺杆菌粘合剂在 Na，K-ATPase下调将被描述。对病毒因子CAGA和CAGPAI的依赖性 将确定4型分泌系统（T4SS）。胃损伤通过Na，K-ATPase下调的作用 从固醇细胞的诱导杆细胞诱导信号通路将在肠道丝菌共培养模型中进行研究。一个 纳米串平台将用于检查细菌中的基因变化，并顺利进行宿主，以便 扩展障碍物障碍的目标，并最终引发肿瘤发生。协调的信号 细菌和宿主诱导的系统影响降低Na，K-ATPase诱导的系统将被描述，特别是 与Cagpai T4SS有关；将探索已知途径，并通过 创新的质谱技术。这项工作的完成将有助于确定幽门螺杆菌的原因和方式 除了通过CAGPAI进入细胞的CAGA以外 影响Na，K-ATPase水平，并描绘细菌因子如何通过宿主蛋白诱导信号传导 级联，导致转运蛋白水平的变化。这项工作的目的是获得新的见解 幽门螺杆菌的胃损伤机理，这将导致新型的治疗保护和治疗选择。