NF-kB Signaling and H. Pylori-induced Gastric Disease

NF-kB 信号传导与幽门螺杆菌诱发的胃病

• 批准号: 8215750
• 负责人: Lin-Feng Chen
• 金额: $ 31.95万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215750
• 关键词: Acetylation; Actins; Address; Bacteria; Binding; Biological Models; Bypass; Cancer Etiology; Cell Nucleus; Cell membrane; Cells; Cellular Membrane; Cessation of life; Chronic Gastritis; Cultured Cells; Cytoplasm; Cytoskeleton; DNA Sequence Rearrangement; Data; Development; Disease; Epithelial Cells; Event; Gastric Adenocarcinoma; Gastritis; Genes; Gerbils; Helicobacter Infections; Helicobacter pylori; Human; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Lead; Link; MAP3K7 gene; Malignant Neoplasms; Mediating; Membrane; Methylation; Modification; Molecular; NF-kappa B; Nuclear; Pharmaceutical Preparations; Phosphorylation; Play; Post-Translational Protein Processing; Property; Proteins; Risk; Risk Factors; Role; Series; Signal Transduction; Signaling Molecule; Signaling Protein; Stimulus; Stomach; Stomach Diseases; System; TRAF6 gene; Testing; Transcriptional Activation; Ulcer; Virulence Factors; base; carcinogenesis; cytokine; in vivo; inhibitor/antagonist; insight; malignant stomach neoplasm; mutant; new therapeutic target; novel; pathogen; public health relevance; receptor; response; transcription factor

DESCRIPTION (provided by applicant): H. pylori infection causes chronic gastritis and peptic ulceration and is the strongest risk factor for the development of gastric cancer. H. pylori-initiated chronic gastritis is characterized by the enhanced expression of proinflammatory cytokines, whose expression is largely mediated by transcription factor NF- kappaB. Activation of NF-kappaB is tightly regulated by cytoplasmic and nuclear events, including the activation of IKK, the degradation of I(B( in the cytoplasm, and the various posttranslational modifications of NF-kappaB in the nucleus. H. pylori virulence factor CagA is injected into epithelial cells via the type 4 secretion system and has long been indicated to be critical for the H. pylori-mediated inflammatory response. H. pylori CagA elicits its various functions by interacting with different host signaling molecules, an event which requires the binding of CagA to the membrane and the oligomerization of CagA. Our recent studies demonstrate that CagA is essential for the H. pylori-induced activation of NF-kappaB and the inflammatory response. However, how the membrane binding and oligomerization properties of CagA contribute to the H. pylori-induced inflammatory response, how CagA hijacks cellular signaling molecules for the activation of NF- kappaB, and how the posttranslational modifications of NF-kappaB regulate the H. pylori-induced inflammatory response remain to be determined. This proposal seeks to explore these important questions. In Specific Aim 1, we will decipher the role of CagA membrane-binding and oligomerization properties in H. pylori-mediated NF-(B activation by examining various membrane-binding and oligomerization- defective mutants of CagA and H. pylori strains harboring these CagA mutants. We will also determine the in vivo function of these properties of CagA by infecting Mongolian gerbils with various H. pylori CagA mutant strains. In Specific Aim 2, we will define whether and how the intracellular host signaling proteins are hijacked by H. pylori virulence factor CagA for the activation of NF-kappaB. We will also determine whether blocking the interaction of CagA with host cell proteins represents an effective approach to inhibit the H. pylori-mediated inflammatory response. In Specific Aim 3, we will define the role of posttranslational modifications of RelA in H. pylori-induced NF-(B activation. In addition, we will assess the interplay between various posttranslational modifications and how these modifications function alone or in combination to control the H. pylori-mediated inflammatory response. Successful accomplishment of these Specific Aims will provide new insights into the role of CagA in the H. pylori-mediated activation of NF-kappaB and identify novel host signaling molecules hijacked by CagA, and will identify new therapeutic targets to mediate the NF- kappaB-dependent inflammatory response through inhibiting the interaction of CagA with host signaling molecules or by modulating the posttranslational modifications of NF-kappaB. PUBLIC HEALTH RELEVANCE: Helicobacter pylori is one of the most wide-spread infections in humans worldwide and H. pylori infection has been shown to be associated with an increased risk of gastric adenocarcinoma, which is linked to infection- initiated chronic gastritis. Our recent studies have shown that H. pylori stimulates the activation of transcription factor NF-kappaB and the inflammatory response in a virulence factor CagA-dependent manner, but the detailed mechanism for this activation remains unclear. Understanding the activation of NF- kappaB by H. pylori will increase our understanding of the molecular basis of NF-kappaB activation, the interaction between pathogens and cellular signaling molecules, and may lead to the identification of specific inhibitors that can be useful drugs for the treatment of H. pylori-initiated inflammatory diseases and cancer.

描述（申请人提供）：幽门螺旋杆菌感染可引起慢性胃炎和消化性溃疡，是胃癌发生的最强危险因素。幽门螺杆菌引发的慢性胃炎以促炎细胞因子的表达增强为特征，促炎细胞因子的表达主要由转录因子NF- κ b介导。NF-kappaB的激活受到细胞质和细胞核事件的严格调控，包括IKK的激活、细胞质中I(B)的降解以及细胞核中NF-kappaB的各种翻译后修饰。幽门螺杆菌毒力因子CagA通过4型分泌系统被注射到上皮细胞中，长期以来被证明对幽门螺杆菌介导的炎症反应至关重要。幽门螺杆菌CagA通过与不同宿主信号分子相互作用来发挥其各种功能，这一事件需要CagA与膜结合并低聚化。我们最近的研究表明，CagA对幽门螺杆菌诱导的NF-kappaB激活和炎症反应至关重要。然而，CagA的膜结合和寡聚化特性如何促进H. pylori诱导的炎症反应，CagA如何劫持细胞信号分子激活NF-kappaB，以及NF-kappaB的翻译后修饰如何调节H. pylori诱导的炎症反应仍有待确定。本提案旨在探讨这些重要问题。