CRISPR Capture, Destroy, and Counter-Attack Mechanisms

项目摘要 CRISPR-Cas适应性免疫系统由原核生物部署，以保护它们免受潜在的 致命的病毒感染。作为一种反防御策略，某些病毒会产生抗CRISPR（ACR）蛋白 能够使CRISPR介导的抗病毒免疫失活。不同的CRISPR-Cas系统通过以下方式发挥作用： 捕获宿主基因组的CRISPR基因座内的短病毒序列并使用表达的crRNA， 相关的Cas核酸酶用于病毒识别和破坏。病毒ACRs的特性和功能 颠覆独特的CRISPR-Cas系统的行为才刚刚被揭露。我们的主要目标 研究计划是：1）了解宿主CRISPR-Cas 病毒的免疫途径和抗CRISPR活性，以及2）利用所获得的知识， 改进基于CRISPR的应用。利用分子，遗传， 结构和生物化学的方法，从一个优秀的合作者团队的宝贵贡献，我们 我们将继续致力于剖析各种CRISPR-Cas的通路并描绘其分子机制， 系统.此外，我们将获得关键的见解ACR介导的机制所使用的病毒，以阻挠 CRISPR免疫。基于CRISPR的创新工具和技术正在为以下领域提供变革性进展： 基础和医学研究。我们的研究所获得的知识将直接有助于正在进行的努力 旨在利用不同的CRISPR-Cas系统作为强大的研究工具（例如用于基因组编辑和 控制基因表达，选择性地检测和靶向人类病毒和细菌病原体， 限制抗生素耐药性的传播）。此外，了解不同的详细作用方式， ACR是必要的，以建立ACR作为重要的新的研究工具，选择性和安全地利用 不同的CRISPR技术。

Project Summary CRISPR-Cas adaptive immune systems are deployed by prokaryotic organisms to protect them from potential lethal infection by viruses. As a counter-defense strategy, certain viruses produce anti-CRISPR (ACR) proteins capable of inactivating CRISPR-mediated, anti-viral immunity. Diverse CRISPR-Cas systems function by capturing short viral sequences within the CRISPR locus of the host genome and using expressed crRNAs and associated Cas nucleases for viral recognition and destruction. The identities and functions of viral ACRs in subverting distinct CRISPR-Cas systems are only just now being revealed. The primary objectives of our research program are: 1) to understand the molecular basis of mechanisms underlying both host CRISPR-Cas immune pathways and anti-CRISPR activities of viruses and 2) to exploit knowledge gained to contribute and improve CRISPR-based applications. Using an established and powerful combination of molecular, genetic, structural and biochemical approaches, with invaluable contributions from a team of superb collaborators, we will continue to work to dissect pathways and delineate molecular mechanisms governing diverse CRISPR-Cas systems. Furthermore, we will gain key insight on ACR-mediated mechanisms used by viruses to thwart CRISPR immunity. Innovative CRISPR-based tools and technologies are providing transformative advances in basic and medical research. The knowledge gained by our research will contribute directly to ongoing efforts aimed at exploiting diverse CRISPR-Cas systems as powerful research tools (e.g. for genome editing and controlled gene expression, to selectively detect and target human viral and bacterial pathogens, and for limiting the spread of antibiotic resistance). Moreover, understanding the detailed modes of action of diverse ACRs is necessary for establishing ACRs as important new research tools for selective and safe utilization of different CRISPR-based technologies.