Mechanisms of induction of gastric injury by H. pylori

幽门螺杆菌诱导胃损伤的机制

基本信息

项目摘要

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流行的病原体,全世界有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 是全球癌症死亡的主要原因之一,根除这种感染将导致预防或 甚至胃癌的消退。由于广泛使用抗生素,治疗变得更加困难。 抵抗。尽管有许多不同的疾病,但目前还不确定谁会继续发展为晚期疾病 细菌和宿主因素也有牵连。这一研究方案的重点是研究机制。 与可能导致胃损伤的新宿主/细菌连接有关。已知幽门螺杆菌可导致 上皮损伤,初步数据表明细菌诱导Na,K-ATPase下调, 它通过建立向内的钠梯度和与细胞 粘附力。胃上皮细胞Na,K-ATPase活性降低导致屏障功能降低 胃部损伤。幽门螺杆菌对转运体的下调针对新形成的泵和来自 急诊室。这一机制将通过对翻译后修饰的潜在研究来进一步研究 由细菌诱导,通过观察泵表达减少对胃的生理后果 细胞,并通过进一步表征泵降解的机制。幽门螺杆菌的细菌因子也起到了 在诱导胃损伤中起重要作用。从细菌的角度来看,幽门螺杆菌的直接黏附在 Na,K-ATPase下调将被勾画出来。对毒力因子CagA和CagPAI的依赖性 将测定第四型分泌系统(T4SS)。Na,K-ATPase下调在胃损伤中的作用 在肠样-基质共培养模型中,将研究来自气孔细胞的信号通路的诱导。一个 纳米串平台将用于同时检测细菌和宿主的基因变化,以便 扩大在屏障障碍和最终启动肿瘤形成方面研究的靶点。协调信令 细菌和宿主诱导的影响Na,K-ATPase下降的系统将被描述为 与CagPAI T4SS相关;将探索已知途径,并通过 创新的质谱学技术。这项工作的完成将有助于确定幽门螺杆菌的原因和方式 特异性靶向Na,K-ATPase,识别除CagA外通过CagPAI进入细胞的效应分子 影响Na,K-ATPase水平,并描述宿主蛋白修饰的细菌因子如何诱导信号 级联作用,导致转运体水平的变化。这项工作的目标是获得对 幽门螺杆菌对胃损伤的机制,这将导致新的治疗保护和治疗选择。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Elizabeth A. Marcus其他文献

Sa1889 <em>Helicobacter pylori</em> Infection and Apical Acidity Alter Transepithelial Resistance, Paracellular Permeability, and Inflammatory Response in Gastric Epithelial Cells
  • DOI:
    10.1016/s0016-5085(13)61199-3
  • 发表时间:
    2013-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Elizabeth A. Marcus;Olga Vagin;Elmira Tokhtaeva;George Sachs;David R. Scott
  • 通讯作者:
    David R. Scott
Intestinal Re-Transplantation
肠再移植
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Carolyn P Smullin;R. Venick;Elizabeth A. Marcus;Suzanne V. McDiarmid;H. Yersiz;Ronald W. Busuttil;Douglas G. Farmer
  • 通讯作者:
    Douglas G. Farmer
The effect of L-arginine on <em>H. pylori</em> bioenergetics and viability
  • DOI:
    10.1016/s0016-5085(00)85066-0
  • 发表时间:
    2000-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    David R. Scott;Elizabeth A. Marcus;George Sachs
  • 通讯作者:
    George Sachs
Mo1264 – <em>Helicobacter Pylori</em> Infection Decreases Na,K-Atpase Expression in Gastric Epithelial Cells by Impairing Chaperone-Assisted Transporter Maturation in the Endoplasmic Reticulum
  • DOI:
    10.1016/s0016-5085(19)38779-7
  • 发表时间:
    2019-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Elizabeth A. Marcus;Elmira Tokhtaeva;Jossue L. Jimenez;Yi Wen;Bita V. Naini;Ashley N. Heard;Samuel Kim;Joseph Capri;Whitaker Cohn;Julian P. Whitelegge;Olga Vag
  • 通讯作者:
    Olga Vag
Urei is the link between intra-bacterial urease of <em>Helicobacter pylori</em> and gastric survival
  • DOI:
    10.1016/s0016-5085(00)84856-8
  • 发表时间:
    2000-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    David L. Weeks;David R. Scott;Sepehr Eskandari;Elizabeth A. Marcus;Nayoung Kim;Marina Rektorschek;Anita Buhmann;Barbara Schmitt;Klaus Melchers;George Sachs
  • 通讯作者:
    George Sachs

Elizabeth A. Marcus的其他文献

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{{ truncateString('Elizabeth A. Marcus', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 40.87万
  • 项目类别:
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:
    10403555
  • 财政年份:
    2021
  • 资助金额:
    $ 40.87万
  • 项目类别:
The role of ArsS in gastric infection by Helicobacter pylori
ArsS在幽门螺杆菌胃部感染中的作用
  • 批准号:
    9461047
  • 财政年份:
    2015
  • 资助金额:
    $ 40.87万
  • 项目类别:
Mechanisms of gastric mucosal response to H. pylori infection at acidic pH
酸性pH下胃粘膜对幽门螺杆菌感染的反应机制
  • 批准号:
    8617107
  • 财政年份:
    2014
  • 资助金额:
    $ 40.87万
  • 项目类别:
Mechanisms of gastric mucosal response to H. pylori infection at acidic pH
酸性pH下胃粘膜对幽门螺杆菌感染的反应机制
  • 批准号:
    8913164
  • 财政年份:
    2014
  • 资助金额:
    $ 40.87万
  • 项目类别:
Mechanisms of gastric mucosal response to H. pylori infection at acidic pH
酸性pH下胃粘膜对幽门螺杆菌感染的反应机制
  • 批准号:
    9119816
  • 财政年份:
    2014
  • 资助金额:
    $ 40.87万
  • 项目类别:
Mechanisms of gastric mucosal response to H. pylori infection at acidic pH
酸性pH下胃粘膜对幽门螺杆菌感染的反应机制
  • 批准号:
    9344597
  • 财政年份:
    2014
  • 资助金额:
    $ 40.87万
  • 项目类别:

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