Understanding host interactions with retroelements using Ty3 as a model system

使用 Ty3 作为模型系统了解宿主与逆转录因子的相互作用

• 批准号: 7546838
• 负责人: Dina Priscilla Matheos
• 金额: $ 5.48万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7546838
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Animals; Anti-Retroviral Agents; Bioinformatics; Biological Models; Cell Cycle; Cell Cycle Arrest; Cell Cycle Inhibition; Cell Cycle Regulation; Cell Nucleus; Cells; Complementary DNA; Complex; DNA; DNA Maintenance; DNA biosynthesis; Data; Development; Disease; Enzymes; Failure; G1 Arrest; Gene Expression; Genes; Genome; Goals; HIV; HIV-1; Homologous Gene; Human; Infection; Integration Host Factors; Knowledge; Lead; Life Cycle Stages; Mammalian Cell; Mus; Mutation; Nature; Nuclear; Organism; Partner in relationship; Pharmaceutical Preparations; Phase; Pheromone; Physiologic pulse; Proliferating; Proteins; Public Health; Pulse taking; RNA; RNA Viruses; RNA-Directed DNA Polymerase; Resistance; Retroelements; Retrotransposon; Retroviridae; Reverse Transcription; Saccharomyces cerevisiae; Saccharomycetales; Source; Staging; Structure; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Viral; Virus; Virus Diseases; Work; Yeasts; extracellular; gene therapy; insight; macrophage; mutant; novel; novel therapeutics; particle; therapeutic target; vector; viral DNA

DESCRIPTION (provided by applicant): Retroviruses are agents of disease in humans and animals, but they also hold the potential to be the vehicles of gene therapy. Retroviruses are RNA viruses that infect a cell, reverse transcribe their RNA into DNA and then integrate their viral DNA into the host genome at which point they are free to replicate and produce more viral particles for further infection. Sixteen million people have died worldwide from AIDS, the causative agent being the HIV retrovirus, and another 50 million people are infected worldwide. All viruses are absolutely dependent on host factors for their proliferation. Understanding which factors are absolutely essential for viral replication could lead the way to developing new therapeutic agents to combat viral infections. The goal of this project is to use yeast and the retrotransposon Ty3 as a model system to identify host functions that affect the retrotansposon lifecycle and potentially the retrovirus lifecycle. Ty3 resembles retroviruses in its genome organization and the proteins encoded. The retrotransposon lifecycle has parallels with the intracellular retroviral lifecycle and differs mainly in that it does not have an extracellular phase. First we are taking advantage of similarities between Ty3 and retroviruses to understand host cell cycle inhibition of reverse transcriptase activity. Reverse transcriptase is one of the most commonly targeted enzymes of anti-retroviral drugs so understanding cell cycle regulation of RT activity could potentially uncover new ways to target and restrict retroviral infection. Second we are characterizing the possible requirements of host S phase checkpoint activation in Ty3 replication. Finally we have used bioinformatics approaches to identify murine homologs of yeast genes known to affect the Ty3 lifecycle. We propose to test the effect these genes have on retroviral replication. Since the retrotransposon and retroviral lifecycles are similar and because of the high degree of conservation between yeast and mammalian genes, this approach may uncover a way to rapidly identity novel cellular factors required for retroviral replication. There are two major ways in which this study could impact public health. Our work may identify host factors in mammalian cells that are important for viral replication and this knowledge could aid in the development of new anti-viral therapeutics. This is an important issue for public health as there are resistant strains of HIV to almost all known drugs. Also our study could provide information crucial in the development of retroviruses for use as vectors to deliver gene therapy treatments by addressing the issues of viral integration into the host cell.

描述(由申请人提供)： 逆转录病毒是人类和动物的疾病媒介，但它们也有可能成为基因治疗的载体。逆转录病毒是一种RNA病毒，它会感染细胞，将其RNA逆转录成DNA，然后将其病毒DNA整合到宿主基因组中，在这一点上，它们可以自由复制并产生更多病毒颗粒，以便进一步感染。全世界已有1600万人死于艾滋病，艾滋病的病原体是艾滋病毒逆转录病毒，全球另有5000万人受到感染。所有病毒的增殖都完全依赖于宿主因素。了解哪些因素对病毒复制是绝对必要的，可能会导致开发新的治疗药物来对抗病毒感染。该项目的目标是使用酵母和逆转录转座子Ty3作为模型系统，以确定影响反转录转座子生命周期和潜在的逆转录病毒生命周期的宿主功能。Ty3在基因组组织和编码的蛋白质上与逆转录病毒相似。反转录转座子的生命周期与细胞内的逆转录病毒的生命周期相似，主要的不同之处在于它没有胞外阶段。首先，我们利用Ty3和逆转录病毒之间的相似性来了解宿主细胞周期对逆转录酶活性的抑制。逆转录酶是抗逆转录病毒药物最常见的靶向酶之一，因此了解RT活性的细胞周期调节可能会发现靶向和限制逆转录病毒感染的新方法。其次，我们正在表征主机S阶段检查点激活在Ty3复制中的可能要求。最后，我们使用生物信息学方法来鉴定已知影响Ty3生命周期的酵母基因的小鼠同源基因。我们建议测试这些基因对逆转录病毒复制的影响。由于逆转录转座子和逆转录病毒的生命周期相似，而且酵母和哺乳动物的基因高度保守，这种方法可能会发现一种快速鉴定逆转录病毒复制所需的新细胞因子的方法。这项研究可能通过两种主要方式影响公众健康。我们的工作可能确定哺乳动物细胞中对病毒复制重要的宿主因子，这一知识可能有助于开发新的抗病毒疗法。这对公共卫生来说是一个重要问题，因为艾滋病毒对几乎所有已知药物都有抗药性。此外，我们的研究还可以通过解决病毒整合到宿主细胞中的问题，为逆转录病毒的发展提供至关重要的信息，以用作提供基因治疗的载体。