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（由申请人提供）：H。幽门螺杆菌感染可引致慢性胃炎及消化性溃疡，是发展成胃癌的最大危险因素。H.幽门启动的慢性胃炎的特征在于促炎细胞因子的表达增强，其表达主要由转录因子NF-κ B介导。NF-κ B的激活受细胞质和细胞核事件的严格调节，包括IKK的激活、细胞质中I（B）的降解以及细胞核中NF-κ B的各种翻译后修饰。H.幽门螺杆菌毒力因子CagA通过4型分泌系统注入上皮细胞，长期以来被认为是幽门螺杆菌的关键因子。幽门介导的炎症反应。H.幽门螺杆菌CagA通过与不同的宿主信号分子相互作用而发挥其多种功能，这一事件需要CagA与膜的结合和CagA的寡聚化。我们最近的研究表明，CagA是H。幽门螺杆菌诱导的NF-κ B活化和炎症反应。然而，CagA的膜结合和寡聚化特性如何影响H。pylori诱导的炎症反应，CagA如何劫持细胞信号分子激活NF-κ B，以及NF-κ B的翻译后修饰如何调节H.幽门诱导炎症反应仍有待确定。本提案旨在探讨这些重要问题。 在具体目标1中，我们将破译CagA膜结合和寡聚化特性在H。pylori介导的NF-（B）活化。pylori菌株携带这些CagA突变体。我们还将通过用不同的H. pylori CagA突变株。在具体目标2中，我们将定义细胞内宿主信号蛋白是否以及如何被H. pylori毒力因子CagA激活NF-κ B。我们还将确定阻断CagA与宿主细胞蛋白的相互作用是否是抑制H.幽门介导的炎症反应。在具体目标3中，我们将定义RelA的翻译后修饰在H. pylori诱导的NF-（B）活化。此外，我们将评估各种翻译后修饰之间的相互作用，以及这些修饰如何单独或联合控制H。幽门介导的炎症反应。这些具体目标的成功实现将为CagA在H.本发明的目的在于研究幽门螺杆菌介导的NF-κ B的活化，并鉴定被CagA劫持的新的宿主信号传导分子，并将鉴定新的治疗靶标以通过抑制CagA与宿主信号传导分子的相互作用或通过调节NF-κ B的翻译后修饰来介导NF-κ B依赖性炎症反应。 公共卫生相关性：幽门螺杆菌是世界范围内人类最广泛的感染之一。幽门螺杆菌感染与胃腺癌的风险增加有关，胃腺癌与感染引起的慢性胃炎有关。我们最近的研究表明，H。pylori刺激转录因子NF-κ B的活化和以毒力因子CagA依赖的方式的炎症反应，但这种活化的详细机制仍不清楚。了解H. pylori的研究将增加我们对NF-κ B激活的分子基础、病原体与细胞信号分子之间的相互作用的理解，并可能导致识别特异性抑制剂，这些抑制剂可作为治疗H.幽门引发的炎性疾病和癌症。