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，并且是胃癌发展的最强危险因素。幽门螺杆菌引起的慢性胃炎的特征是促炎细胞因子的表达增强，其表达在很大程度上是由转录因子NF-kappab介导的。 NF-kappab的激活受细胞质和核事件的严格调节，包括IKK的激活，I（b（b（在细胞质中，以及NF-kappab）在核中的NF-kappab的各种nf-kappab的转换后修饰。幽门螺杆菌介导的炎症反应。幽门螺杆菌通过与不同的宿主信号分子相互作用。 CAGA的寡聚特性有助于幽门螺杆菌诱导的炎症反应，CAGA如何劫持了NF-KAPPAB激活的细胞信号传导分子以及NF-KAPPAB的翻译后修饰如何调节H. Pylori诱导的炎症反应。该建议旨在探索这些重要问题。 在特定目的1中，我们将解释幽门螺杆菌介导的Nf-在幽门螺杆菌介导的Nf-中的CAGA膜结合和寡聚特性的作用（B通过检查CAGA和H.幽门螺杆菌的各种膜结合和寡聚 - 有缺陷的突变体的激活。在特定目标2中，带有各种幽门螺杆菌的幽门螺杆菌菌株的香鼠。在特定的目标3中，我们将定义RELA的翻译后修饰的作用（B激活。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在控制H. Pylori介导的炎症反应中的作用。这些特定目标的成功完成将为CAGA在幽门螺杆菌介导的NF-KAPPAB激活中的作用提供新的见解，并确定由CAGA劫持的新型宿主信号分子，并将确定新的治疗靶标，并通过抑制NF-KAPPAB依赖的炎症反应来识别与CAGAN的相互作用或通过CORCAGA的互联型相互作用的摩西群体互联网，以识别caga的新宿主信号分子。 NF-kappab的修改。 公共卫生相关性：幽门螺杆菌是全球人类最广泛的感染之一，幽门螺杆菌感染已被证明与胃腺癌的风险增加有关，这与感染引发的慢性胃炎有关。我们最近的研究表明，幽门螺杆菌刺激转录因子NF-kappab的激活和以毒力因子CAGA依赖性方式激活，但这种激活的详细机制尚不清楚。了解幽门螺杆菌对NF-KAPPAB的激活将增加我们对NF-kappab激活的分子基础的理解，病原体与细胞信号分子之间的相互作用，并可能导致鉴定有用的特定抑制剂，这些抑制剂可作为幽门螺杆菌引起的炎症性疾病和癌症的治疗。