Role for polyamines in Ebola Virus Replication

多胺在埃博拉病毒复制中的作用

基本信息

批准号：
9018817
负责人：
John H Connor
金额：
$ 24.63万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9018817
关键词：
Address Advanced Development Amino Acids Animal Disease Models Animal Model Animals Antiviral Therapy Biochemistry Biology Cell physiology Cells Cellular biology Charge Clinic DNA Viruses Data Dependence Disease Disease Outbreaks Drug Targeting Ebola Hemorrhagic Fever Ebola virus Ebola-like Viruses Effectiveness Elongation Factor Enzymes Excision FDA approved Family Fatality rate Filoviridae Filovirus Frankfurt-Marburg Syndrome Virus Gene Expression Gene Targeting Genes Genetic Goals Health Human In Vitro Infection Integration Host Factors Lead Link Magic Mammalian Cell Panic Pathogenesis Pathway interactions Play Polyamines Polymerase Process Protein Biosynthesis Proteins Retroviridae Role Satellite Viruses Structure System Technology Testing Theft Therapeutic Translations Vaccines Veins Viral Viral Genes Virus Virus Replication Western Africa Work base cancer cell combat eIF-5A hypusine in vivo insight knock-down molecular targeted therapies pathogen public health relevance research study small molecule stem treatment program virus host interaction

Address Advanced Development Amino Acids Animal Disease Models Animal Model Animals Antiviral Therapy Biochemistry Biology Cell physiology Cells Cellular biology Charge Clinic DNA Viruses Data Dependence Disease Disease Outbreaks Drug Targeting Ebola Hemorrhagic Fever Ebola virus Ebola-like Viruses Effectiveness Elongation Factor Enzymes Excision FDA approved Family Fatality rate Filoviridae Filovirus Frankfurt-Marburg Syndrome Virus Gene Expression Gene Targeting Genes Genetic Goals Health Human In Vitro Infection Integration Host Factors Lead Link Magic Mammalian Cell Panic Pathogenesis Pathway interactions Play Polyamines Polymerase Process Protein Biosynthesis Proteins Retroviridae Role Satellite Viruses Structure System Technology Testing Theft Therapeutic Translations Vaccines Veins Viral Viral Genes Virus Virus Replication Western Africa Work base cancer cell combat eIF-5A hypusine in vivo insight knock-down molecular targeted therapies pathogen public health relevance research study small molecule stem treatment program virus host interaction

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项目摘要

DESCRIPTION (provided by applicant): The Filoviridae are a small family of viruses that include the highly pathogenic Ebola and Marburg viruses. These viruses are associated with fatality rates of up to 90%. As has been highlighted during the recent outbreaks of Ebola in Western Africa, filoviruses have tremendous potential for adverse health effects both directly (through direct pathogenesis) and indirectly (forcing the shutdown of existing clinics and treatment programs, sparking panic). Though a variety of potential therapies for the disease have been developed and deployed, it is currently unclear which if any have helped. A clear lesson from the outbreak is that the lack of basic information about viruses like Ebola have hampered effective control and therapy. In this vein, it is clear that basic aspects of how Ebola and its relatives utilize components of infected cells to their advantage are still unknown. A detailed understanding of how Ebola "steals" from its host or identification of cellular processes that the virus requires can offer important insight into both the general biology of the virus and can lead to the identification of host processes that can be effectively targeted to block viral replication. This proposal will test the hypothesis that polyamines and products of polyamines such as the non-canonical amino acid hypusine are essential for Ebola virus replication. To test this hypothesis we will use existing small- molecules that target the polyamine synthesis pathway and we will use gene-targeting knockdown technology to assess the importance of polyamine synthesis enzymes, hypusination enzymes and the hypusinated protein eIF5A on Ebola virus gene expression. Through these studies we hope to determine the importance of this pathway for viral gene expression and understand the mechanism by which the polyamine pathway controls viral gene expression. Identification of this pathway as important for Ebola virus replication has significant translational implications, as there are many compounds that are known to target the polyamine and hypusine synthesis pathways. Some of these are FDA-approved, some are in advanced development. Data supporting our hypothesis that this pathway is important can lead to the testing of these compounds in animal models of disease.

描述（由适用提供）：Filoviridae是一个小型病毒，其中包括高度致病性的埃博拉病毒和Marburg病毒。这些病毒与高达90％的死亡率有关。正如最近在西非最近发生的埃博拉病毒爆发期间所强调的那样，丝状病毒具有直接（通过直接发病机理）和间接的（迫使现有诊所和治疗计划的关闭，引发恐慌）具有巨大的不良健康影响潜力。尽管已经开发和部署了各种疾病的潜在疗法，但目前尚不清楚哪些有帮助。暴发疫情的一个明显的教训是，缺乏有关埃博拉病毒的基本信息阻碍了有效的控制和治疗。在这种情况下，很明显，埃博拉病毒及其亲戚如何利用感染细胞的组成部分来利用其优势的基本方面仍然未知。对埃博拉病毒所需的细胞过程“偷窃”的详细理解可以为病毒的一般生物学提供重要的见解，并可以导致识别宿主过程，以有效地靶向以阻断病毒复制。该提案将检验以下假设：多胺（例如非典型氨基酸）的多胺和产物对于埃博拉病毒复制至关重要。检验该假设，我们将使用靶向多胺合成途径的现有小分子，我们将使用基因靶向敲低技术来评估多胺合成酶，非偶然酶和未休息的蛋白EIF5A对埃博拉病毒基因表达的重要性。通过这些研究，我们希望确定该途径对病毒基因表达的重要性，并了解多胺途径控制病毒基因表达的机制。鉴定该途径对于埃博拉病毒复制很重要，具有显着的转化含义，因为许多化合物已知可以靶向多胺和非肌关系合成途径。其中一些是FDA批准的，有些是在高级开发中。支持我们的假设的数据，即这种途径很重要，可以导致在疾病动物模型中对这些化合物进行测试。