Potential Role of H. Pylori-induced MIF in Gastric Cancer

幽门螺杆菌诱导的 MIF 在胃癌中的潜在作用

• 批准号: 7629624
• 负责人: Ellen J. Beswick
• 金额: $ 0.77万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629624
• 关键词: Address; Antigen-Presenting Cells; Apoptosis; Bacteria; Binding; Blocking Antibodies; Cancer Etiology; Carcinogens; Cell Cycle Kinetics; Cell Surface Proteins; Cell surface; Cells; Cessation of life; Chronic Gastritis; Complement Factor H; Cytoplasmic Tail; Data; Developed Countries; Developing Countries; Development; Disease; Duodenal Ulcer; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Event; Exposure to; Fibroblasts; Genes; Health Care Costs; Helicobacter Infections; Helicobacter pylori; Human; Immigration; Immune System Diseases; Immune response; Immunoprecipitation; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Intracellular Transport; Island; Kinetics; Knock-out; Link; MHC Class II Genes; Malignant Neoplasms; Measures; Mediator of activation protein; Membrane Microdomains; Migration Inhibitory Factor; Natural Immunity; Pathogenesis; Pathogenicity Island; Phosphoproteins; Phosphorylation; Play; Population; Production; Pylorus; Recombinants; Research Personnel; Risk; Role; Signal Transduction; Stomach; Stomach Carcinoma; Surface; Testing; Virulence Factors; Virulent; Western Blotting; World Health Organization; carcinogenesis; cell motility; cyclooxygenase 2; cytokine; in vivo; inhibitor/antagonist; insight; invariant chain; malignant stomach neoplasm; neutralizing antibody; novel; pathogen; phenylpyruvate tautomerase; receptor; receptor expression; response; therapeutic target

DESCRIPTION (provided by applicant): Helicobacter pylori is one of the world's most widespread human pathogens, infecting more than 50% of the population. This pathogen is the major contributor to gastric cancer, which is the second leading cause of cancer deaths in the world. H. pylori induces macrophage migration inhibitory factor (MIF) production from gastric epithelial cells, and MIF production is an important factor in many cancers. A receptor for MIF is CD74, which I have shown to be highly expressed both in vivo and in vitro, and is upregulated by H. pylori. CD74 has also been shown to be highly expressed in a variety of cancers and is being studied as a therapeutic target in both cancer and immunologic diseases. The finding that H. pylori upregulates CD74, along with the ability of H. pylori to induce MIF, and the role MIF plays promoting carcinogenesis led to the hypothesis that: Helicobacter pylori induces gastric epithelial cell production of MIF, which binds to surface-expressed CD74 resulting in pro-carcinogenic signaling. The specific aims to address this hypothesis are: AIM 1. To characterize the mechanisms involved in H. pylori-induced gastric epithelial cell MIF production where the kinetics, the bacterial factors, and the signaling involved in MIF production will be assessed. AIM 2. To determine the role of CD74 in the interaction of MIF with gastric epithelial cells and whether this binding induces signaling events associated with H. pylori infection. The role of CD74 as the receptor for MIF on gastric epithelial cells will be examined along with the presence of any other receptors MIF may utilize. The ability of MIF-bound CD74 to modulate signaling typically seen during H. pylori infection will also be investigated. AIM 3. To determine the role of MIF binding to CD74 on gastric epithelial cell pro-carcinogenic signaling and proliferation. The kinetics of proliferation and apoptosis will be compared with virulent bacteria, strains with deleted cag, anti-CD74 blocking antibodies, and anti-MIF neutralizing antibodies. The effects of MIF on cell cycle kinetics will be examined. These studies will provide valuable insight into cell signaling and responses that are crucial in both inflammation and the development of gastric cancer.

描述（由申请人提供）：幽门螺杆菌是世界上最广泛的人类病原体之一，感染超过 50% 的人口。这种病原体是胃癌的主要原因，而胃癌是世界上第二大癌症死亡原因。幽门螺杆菌诱导胃上皮细胞产生巨噬细胞迁移抑制因子（MIF），而MIF的产生是许多癌症的重要因素。 MIF 的受体是 CD74，我已经证明它在体内和体外都高度表达，并且被幽门螺杆菌上调。 CD74 也已被证明在多种癌症中高表达，并且正在作为癌症和免疫疾病的治疗靶点进行研究。幽门螺杆菌上调 CD74，以及幽门螺杆菌诱导 MIF 的能力以及 MIF 促进致癌作用的发现，导致了这样的假设：幽门螺杆菌诱导胃上皮细胞产生 MIF，MIF 与表面表达的 CD74 结合，从而产生促癌信号传导。解决这一假设的具体目的是： 目的 1. 表征幽门螺杆菌诱导的胃上皮细胞 MIF 产生所涉及的机制，其中将评估 MIF 产生所涉及的动力学、细菌因素和信号传导。目的 2. 确定 CD74 在 MIF 与胃上皮细胞相互作用中的作用，以及这种结合是否诱导与幽门螺杆菌感染相关的信号事件。 CD74 作为 MIF 受体在胃上皮细胞上的作用将与 MIF 可能利用的任何其他受体的存在一起进行检查。还将研究 MIF 结合的 CD74 调节幽门螺杆菌感染期间常见信号的能力。目的 3. 确定 MIF 与 CD74 结合对胃上皮细胞致癌信号传导和增殖的作用。将增殖和凋亡动力学与强毒细菌、删除 cag 的菌株、抗 CD74 阻断抗体和抗 MIF 中和抗体进行比较。将检查 MIF 对细胞周期动力学的影响。这些研究将为细胞信号传导和反应提供有价值的见解，这些信号传导和反应在炎症和胃癌的发展中都至关重要。