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: 7766467
• 负责人: Lin-Feng Chen
• 金额: $ 36.4万
• 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/7766467
• 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; 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; Pylorus; 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）：幽门螺杆菌感染会导致慢性胃炎和消化性溃疡，并且是发展成胃癌的最强危险因素。 H. pylori 引发的慢性胃炎的特点是促炎细胞因子表达增强，其表达主要由转录因子 NF-κB 介导。 NF-kappaB 的激活受到细胞质和核事件的严格调控，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 型分泌系统注射到上皮细胞中，长期以来被认为对于 幽门螺杆菌介导的炎症反应。幽门螺杆菌 CagA 通过与不同的宿主信号分子相互作用来激发其各种功能，这一事件需要 CagA 与膜的结合以及 CagA 的寡聚化。我们最近的研究表明，CagA 对于幽门螺杆菌诱导的 NF-κB 激活和炎症反应至关重要。然而，膜如何结合 CagA 和寡聚特性有助于幽门螺杆菌诱导的炎症反应，CagA 如何劫持细胞信号分子以激活 NF-κB，以及 NF-κB 的翻译后修饰如何调节幽门螺杆菌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。 在具体目标 1 中，我们将通过检查 CagA 的各种膜结合和寡聚化缺陷突变体以及含有这些 CagA 突变体的幽门螺杆菌菌株来破译 CagA 膜结合和寡聚化特性在幽门螺杆菌介导的 NF-(B 激活中的作用。我们还将通过感染蒙古人来确定 CagA 这些特性的体内功能 带有各种幽门螺杆菌 CagA 突变株的沙鼠。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幽门螺杆菌毒力因子 CagA 劫持以激活 NF-kappaB。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幽门螺杆菌介导的炎症的有效方法。 回应。在具体目标 3 中，我们将定义 RelA 翻译后修饰在幽门螺杆菌诱导的 NF-(B 激活中的作用。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组合发挥作用来控制幽门螺杆菌介导的炎症反应。这些具体目标的成功实现将为了解 CagA 在幽门螺杆菌诱导的 NF-(B 激活中的作用)提供新的见解。 幽门螺杆菌介导的 NF-kappaB 激活，识别被 CagA 劫持的新宿主信号分子，并将通过抑制 CagA 与宿主信号分子的相互作用或通过调节 NF-kappaB 的翻译后修饰来识别新的治疗靶点，以介导 NF-kappaB 依赖性炎症反应。 公共卫生相关性：幽门螺杆菌是全世界人类中传播最广泛的感染之一，幽门螺杆菌感染已被证明与胃腺癌风险增加有关，而胃腺癌又与感染引发的慢性胃炎有关。我们最近的研究表明，H. pylori 以毒力因子 CagA 依赖性方式刺激转录因子 NF-kappaB 的激活和炎症反应，但这种激活的详细机制仍不清楚。了解幽门螺杆菌对 NF-kappaB 的激活将增加我们对 NF-kappaB 激活的分子基础、病原体与细胞信号分子之间相互作用的理解，并可能导致鉴定出可作为治疗幽门螺杆菌引发的炎症性疾病和癌症的有用药物的特异性抑制剂。