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Genetic Analysis of Resistance to Viral Infection

抗病毒感染的遗传分析

基本信息

批准号：
9087128
负责人：
BRUCE A BEUTLER
金额：
$ 262.77万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087128
关键词：
Adaptor Protein Complex 3 Adaptor Signaling Protein Address Affect Age Alleles Antiviral Agents Antiviral Response Area Autophagocytosis Biochemical Bunyavirus Infections CRSP3 gene Categories Cell physiology Cells Cellular Stress Cessation of life Child Communication Communities Competence Complex Computer Simulation Cryopreservation Cytomegalovirus Cytomegalovirus Infections DNA Dendritic Cells Derivation procedure Drosophila genus Elements Embryo Endosomes Extended Family Fibroblasts Funding Gene Expression Gene Targeting Generations Genes Genetic Genetic Materials Genetic Techniques Genomic DNA Goals Grant Gray unit of radiation dose HIV Health Herpesviridae Infections Homologous Gene Host Defense Host resistance Human I-kappa B Proteins Image Immune Immune response Immune system Individual Infection Insecta Institutes Interferon Type I Interferons Investigation Knock-out Knockout Mice Learning Life Lipopolysaccharides Mammalian Cell Mammals Maps Massive Parallel Sequencing Measures Mediating Medical center Medicine Membrane Protein Traffic Memory Methods Microbe Modeling Molecular Movement Murid herpesvirus 1 Mus Mutagenesis Mutation Natural Immunity Natural Killer Cells Natural regeneration Nucleic Acids Organism Participant Pathway interactions Pharmaceutical Preparations Physiology Pluripotent Stem Cells Population Post-Transcriptional Regulation Post-Translational Protein Processing Predisposition Principal Investigator Process Productivity Proliferating Proteins RNA RNA Interference Reaction Reagent Recording of previous events Regulation Research Resistance Resistance to infection Resolution Rift Valley fever virus Risk Role Signal Pathway Signal Transduction Small RNA Smallpox Speed Sting Injury Structural Models Systemic Lupus Erythematosus TLR7 gene Talents Technology Therapeutic Time Toll-like receptors Transcriptional Regulation Transmembrane Transport Universities Ursidae Family Vaccines Viral Viral Genes Viral Pathogenesis Virus Virus Diseases Work Writing Zinc Fingers antiviral immunity base combat coping deep sequencing design expression cloning fly forward genetics gene induction gene interaction genetic analysis genome sequencing human disease human mortality induced pluripotent stem cell member molecular targeted therapies mutant mutation screening new technology pathogen pressure prevent programs receptor resistance gene resistance mechanism response reverse genetics screening sensor simulation small molecule sound stem cell technology transcription factor viral DNA viral RNA whole genome

项目摘要

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.

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。