Genetic Analysis of Resistance to Viral Infection

描述(由申请人提供)：本申请扩展了对宿主对病毒感染的抵抗力的成功的多方面调查。我们方法的优势包括：1)基于突变的无偏见组件与假说驱动的组件相结合；2)研究远亲生物(小鼠和果蝇)，以了解哪些防御元件是保守的；3)采用新的强大的方法来支持我们的努力。到目前为止，在我们的工作中，我们已经集体确定了激活抗病毒防御所需的新传感器(例如，LGP2；DICER-2)，并描绘了在生化水平和细胞间通信方面对病毒做出反应的途径。我们已经确定了以前未知的分子参与者 在宿主防御中。其中包括通道蛋白(SLC15A4；KCNJ8/SUR2)、转录因子(IKB；AKIRIN2)、与膜运输或细胞器移动有关的蛋白(AP3B1；STING；TR1M56；ATG9A；UNC93B)、细胞应激(SLFN2)、翻译后修饰(TRIM56；TR1M23)和内体生理学(SLC15A4)。其中一些蛋白质是大家庭的成员，可能会为更广泛的新寄主防御模式开辟道路。其他人则强调了宿主防御的中间步骤(例如，分子在细胞内的运动)的重要性，这是以前从未考虑过的。每个参与小组(达拉斯、大阪和斯特拉斯堡)都有自己的特殊才能，这些天赋结合在一起，使我们超越了遗传学本身，结合了新技术，将加速发现宿主防御机构的基本要素。我们认识到，仅仅拥有一份部件清单是不够的，以了解机器是如何运行的。随着新的蛋白质被证明对宿主防御的特定方面至关重要，我们将确定它们如何相互作用和/或其他蛋白质来支持抗性；它们如何在细胞内催化特定的反应，以及它们如何在我们认为是一个高度动态的过程中驱动或抑制基因的表达。我们认为，这一POL的延续是一个机会，可以在现有生产力的基础上建立一种方法：一种产生了供整个科学界使用的新分子、概念和试剂的方法。波兰人一直是，并将继续在交流方法、遗传物质，以及最重要的、最终源于遗传学的想法方面进行高度合作。

DESCRIPTION (provided by applicant): The present application extends a successful multifaceted investigation of host resistance to viral infection. The strengths of our approach include: 1) an unbiased component based on mutagenesis combined with a hypothesis-driven component; 2) the study of distantly related organisms (mice and Drosophila) to appreciate which elements of defense are conserved; 3) the embrace of new and powerful methods to support our efforts. In our work to date, we have collectively identified new sensors (e.g., LGP2; DICER-2) necessary for activation of antiviral defenses, and delineated pathways of response to viruses, both at a biochemical level and in terms of communication between cells. We have identified previously unknown molecular participants in host defense. Among these are channel proteins (SLC15A4; KCNJ8/SUR2), transcription factors (IKB;AKIRIN2), proteins concerned with membrane trafficking or organellar mobility (AP3B1; STING; TR1M56; ATG9A; UNC93B), cell stress (SLFN2), post-translational modification (TRIM56; TR1M23), and endosome physiology (SLC15A4). Some of these proteins are members of extended families and may open the way to broad new models of host defense. Others highlight the importance of intermediary steps in host defense (e.g., the movement of molecules within cells) in a way that has not been considered before. Each participating group (Dallas, Osaka, and Strasbourg) has its special talents, and these have been combined to take us beyond genetics per se, incorporating new technologies that will accelerate the discovery of essential elements of the host defense apparatus. We recognize that it is not enough to possess a list of parts to understand how a machine operates. As new proteins are shown to be essential for particular aspects of host defense, we will establish how they interact with one another and/or other proteins to support resistance; how they catalyze particular reactions within cells, and how they drive or suppress the expression of genes in what we see as a highly dynamic process. We view the continuation of this POl as an opportunity to build upon an approach with established productivity: one that has generated new molecules, concepts, and reagents for use by the scientific community as a whole. The POl has been, and will continue to be, highly collaborative in the exchange of methods, genetic materials, and most importantly, ideas, ultimately derived from genetics.