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: 8606211
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606211
• 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.

描述(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，是导致胃癌的最大危险因素。幽门螺杆菌感染的慢性胃炎以促炎细胞因子表达增强为特征，其表达在很大程度上由转录因子NF-kappaB介导。核因子-kappaB的激活受到细胞质和核事件的严格调控，包括ikk的激活，胞浆中I(B)的降解，以及核内核因子-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，长期以来一直被认为是幽门螺杆菌介导的炎症反应的关键。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不同的功能，这一过程需要CagA与细胞膜的结合和CagA的寡聚。我们最近的研究表明，CagA在幽门螺杆菌诱导的核因子-kappaB的激活和炎症反应中是必不可少的。然而，CagA的膜结合和寡聚化特性如何在幽门螺杆菌诱导的炎症反应中起作用，CagA如何劫持细胞信号分子以激活核因子-kappaB，以及核因子-kappaB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。 在特定的目标1中，我们将通过检测含有CagA和H.Pylori突变株的各种膜结合和寡聚缺陷突变来破译CagA膜结合和寡聚化特性在H.Pylori介导的NF-B激活中的作用。我们还将通过用不同的幽门螺杆菌CagA突变株感染蒙古沙土鼠来确定CagA的这些特性在体内的功能。在特定的目标2中，我们将确定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劫持以激活核因子-kappaB。我们还将确定阻断CagA与宿主细胞蛋白的相互作用是否代表着抑制幽门螺杆菌介导的炎症反应的有效方法。在特定的目标3中，我们将确定relA的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联合作用来控制幽门螺杆菌介导的炎症反应。这些特定目的的成功实现将为深入了解CagA在幽门螺杆菌介导的NF-kappaB活化中的作用提供新的见解，并将识别被CagA劫持的新的宿主信号分子，并将发现新的治疗靶点，通过抑制CagA与宿主信号分子的相互作用或通过调节NF-kappaB的翻译后修饰来介导依赖于NF-kappaB的炎症反应。