The Sumoylation System as a Novel Target for Anti-Influenza Therapies

Sumoylation 系统作为抗流感治疗的新靶点

• 批准号: 7661477
• 负责人: German Rosas-Acosta
• 金额: $ 11.1万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-21 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661477
• 关键词: Adenovirus Vector; Adenoviruses; Affect; American; Biological Assay; Cell Death; Cell physiology; Cells; Cessation of life; Data; Development; Drug Delivery Systems; Epitopes; Evolution; Exhibits; Foundations; Genes; Goals; Hospitalization; Human; Immune Sera; Immunoblotting; In Vitro; Infection; Influenza; Invaded; Lead; Life Cycle Stages; Methods; Modification; Pathway interactions; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Production; Property; Proteins; Proteomics; Research; Resistance; Resistance development; Role; Scourge; Signal Transduction; System; Testing; Transfection; Ubiquitin; United States; United States National Institutes of Health; Vaccination; Vaccine Production; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; anti-influenza; base; cellular targeting; flexibility; influenza virus vaccine; influenzavirus; innovation; interest; killings; novel; pandemic influenza; prevent; tool

DESCRIPTION (provided by applicant): Influenza still represents one of the most dreadful human scourges. Complications associated to influenza infections are calculated to kill approximately 36,000 Americans every year. Vaccination and current anti-viral drugs have proven useful in preventing fatal complications upon influenza infection. However, the imminent evolution of new pandemic influenza strains likely to be resistant to current anti-viral drugs and the intrinsic technical limitations associated to current vaccine production methods underscore the urgent need to develop novel anti-influenza therapies. Anti-viral therapies that block or enhance cellular processes essential or detrimental for viral replication are significantly less prone to development of resistant viruses. Additionally, by affecting cellular pathways used by the virus, such therapies are more likely to work independently of the type, strain, and antigenic properties of the invading virus. Therefore, such therapies constitute ideal anti-influenza strategies. Here, we hypothesize that augmenting the activity of the sumoylation system, a cellular post-translational modification system, will inhibit influenza virus multiplication. The objective of this study is to evaluate the relevance of sumoylation for influenza virus infection, with the ultimate goal of determining whether the sumoylation system provides new targets for novel anti-influenza therapies. To this end, we will pursue two specific aims: (1) characterize the full array of influenza viral proteins that are sumoylated during infection, and (2) determine the effect of modulating the activity of the host cell sumoylation system on influenza virus multiplication. To achieve these goals, we will utilize a combination of proteomic methods, transient and stable transfection approaches, and adenovirus expression systems. The proposed assays will provide conclusive data on the effect of modulating sumoylation during influenza infections, and give meaningful hints to the effect of sumoylation on the life cycle of the virus. Additionally, the tools developed during the proposed studies will allow the effects of modulating the sumoylation system to be tested on other viruses. This research is highly innovative because the relevance of the sumoylation system for influenza and other viral infections remains unexplored. It is also of great urgency as it could lead to the development of novel anti-influenza therapies potentially applicable to the treatment of pandemic flu and other viral diseases. Furthermore, attaining the proposed goals will also provide the PI with the foundation and preliminary data required for crafting competitive NIH R01 proposals.

描述（由申请人提供）：流感仍然是最可怕的人类祸害之一。据计算，流感感染相关并发症每年导致约 36,000 名美国人死亡。疫苗和当前的抗病毒药物已被证明可有效预防流感感染引起的致命并发症。然而，新的大流行性流感毒株即将进化，可能对当前的抗病毒药物产生耐药性，以及与当前疫苗生产方法相关的内在技术限制，强调了开发新型抗流感疗法的迫切需要。阻断或增强对病毒复制至关重要或有害的细胞过程的抗病毒疗法显着降低了产生耐药病毒的可能性。此外，通过影响病毒使用的细胞途径，此类疗法更有可能独立于入侵病毒的类型、毒株和抗原特性而发挥作用。因此，此类疗法构成了理想的抗流感策略。 在这里，我们假设增强苏酰化系统（一种细胞翻译后修饰系统）的活性将抑制流感病毒的增殖。本研究的目的是评估SUMO化与流感病毒感染的相关性，最终目标是确定SUMO化系统是否为新型抗流感疗法提供新靶点。为此，我们将追求两个具体目标：（1）表征感染过程中苏酰化的全部流感病毒蛋白，以及（2）确定调节宿主细胞苏酰化系统活性对流感病毒增殖的影响。 为了实现这些目标，我们将结合使用蛋白质组学方法、瞬时和稳定转染方法以及腺病毒表达系统。所提出的测定将提供有关流感感染期间调节苏酰化作用的结论性数据，并为苏酰化对病毒生命周期的影响提供有意义的提示。此外，在拟议研究期间开发的工具将允许在其他病毒上测试调节苏素化系统的效果。这项研究具有高度创新性，因为苏素化系统与流感和其他病毒感染的相关性尚未得到探索。它也非常紧迫，因为它可能导致新型抗流感疗法的开发，可能适用于治疗大流行性流感和其他病毒性疾病。此外，实现拟议目标还将为 PI 提供制定有竞争力的 NIH R01 提案所需的基础和初步数据。