Project 3: Genomic and chemical approaches for discovering novel anti-poxvirus strategies

项目总结 天花病毒可导致致命的人类和动物疾病，如天花和猴痘，并有 有可能被用作生物武器。它们也被广泛用作疫苗的表达载体。 发展。目前还缺乏FDA批准的治疗痘病毒感染的药物。的发展。 预防和治疗痘病毒感染的新战略将允许对 人类和动物中痘病毒感染构成的当前和再次出现的威胁。我们在这个项目中的目标 是发现宿主细胞成分和机制，这些成分和机制对于调节病毒复制和 制定策略，使用基因组和化学方法的组合在我们的 学习。对于我们的基因组方法，我们将监测痘病毒中全球蛋白质翻译潜力的变化- 被感染的细胞通过同时和 对总mRNAs和核糖体相关mRNAs进行定量深度测序。我们还将使用一种化学物质 筛选可抑制痘病毒复制的化合物并确定其对 通过基因组学方法鉴定宿主细胞的功能。该方法也可应用于其他医学领域 相关病毒。我们将使用痘病毒家族的原型成员--牛痘病毒。具体而言 目的1，我们将确定潜在的细胞成分和调控痘苗病毒复制的途径。在……里面 具体目标2，我们将发现新型的痘苗病毒复制化学抑制剂并检测它们的效果 通过相对翻译效率分析确定细胞途径和功能。一个主要的 这些努力的结果是获得了有力支持更机械化的假说的观察和数据 驱动的提案仍然以特定细胞功能调节病毒复制这一基本假设为中心 并且这些在全局蜂窝关闭期间被优先翻译。随着对主持人翻译的研究 对痘病毒感染的反应以及痘病毒复制中的细胞功能，我们还将深入了解 痘病毒-宿主的动态相互作用，进而可以导致预防和 病毒感染的治疗策略以及更好的基于痘病毒的疫苗和递送载体的设计。

PROJECT SUMMARY Poxviruses can cause deadly human and animal diseases, such as smallpox and monkeypox, and have the potential to be used as biological weapons. They are also extensively used as expression vectors for vaccine development. There is a lack of FDA-approved drugs for poxvirus-infection treatment. The development of novel strategies to prevent and treat poxvirus infections will allow for responsive treatment and management of current and re-emergent threatens posed by poxvirus infections in human and animals. Our goal in this project is to discover host cell components and mechanisms that are essential for modulating viral replication and develop strategies to disrupt these processes using a combination of genomic and chemical approaches in our studies. For our genomic approach, we will monitor global protein translation potential change in poxvirus- infected cells to identify potential cellular functions important for poxvirus replication by simultaneously and quantitatively deep sequencing total mRNAs and ribosome-associated mRNAs. We will also use a chemical approach to screen for compounds that can inhibit poxvirus replication and determine their effects on the identified host cell functions through the genomic approach. The approach may be applied to other medically relevant viruses. We will use vaccinia virus, the prototype member of poxvirus family in this study. In Specific Aim 1, we will identify potential cellular components and pathways that modulate vaccinia virus replication. In Specific Aim 2, we will discover novel chemical inhibitors of vaccinia virus replication and examine their effects on the cellular pathways and functions identified through relative translation efficiency analysis. A primary outcome of these efforts is to obtain observations and data that strongly support more mechanistic, hypothesis driven proposal still centered on the primary hypothesis that specific cellular functions modulate viral replication and these are preferentially translated during global cellular shutoff. With the study of the host translation responses to poxvirus infection and the cellular functions in poxvirus replication, we will also gain insights into the dynamic poxvirus-host interactions, which in turn, can lead to the development of preventive and therapeutic strategies for viral infections and the design of better poxvirus-based vaccines and delivery vectors.