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

项目摘要 痘病毒可引起致命的人类和动物疾病，如天花和猴痘， 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 发展缺乏FDA批准的用于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策略将允许响应性治疗和管理 痘病毒感染在人类和动物中造成的当前和再次出现的威胁。我们这个项目的目标 是发现调节病毒复制所必需的宿主细胞成分和机制， 在我们的研究中，我们将结合基因组和化学方法来制定破坏这些过程的策略。 问题研究对于我们的基因组方法，我们将监测痘病毒的全球蛋白质翻译潜在变化- 感染的细胞，以鉴定对痘病毒复制重要的潜在细胞功能， 定量深度测序总mRNA和核糖体相关mRNA。我们还将使用一种化学物质 一种筛选能够抑制痘病毒复制的化合物并确定其对 通过基因组方法鉴定宿主细胞功能。该方法可以应用于其他医学领域。 相关病毒本研究将使用痘病毒家族的原型成员牛痘病毒。在特定 目的1，我们将确定潜在的细胞成分和途径，调节牛痘病毒复制。在 具体目标2，我们将发现新的化学抑制剂牛痘病毒复制和检查他们的影响 通过相对翻译效率分析确定的细胞途径和功能。主 这些努力的结果是获得观测结果和数据，这些观测结果和数据强烈支持更机械的假设， 一个有驱动力的提议仍然集中在特定细胞功能调节病毒复制的基本假设上 并且这些在全局细胞关闭期间优先被翻译。随着对主持翻译的研究 对痘病毒感染的反应和痘病毒复制中的细胞功能，我们还将深入了解 动态痘病毒-宿主相互作用，这反过来又可以导致预防性和 病毒感染的治疗策略以及更好的痘病毒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.