Genetic Analysis of Resistance to Viral Infection

抗病毒感染的遗传分析

• 批准号: 8513871
• 负责人: BRUCE A BEUTLER
• 金额: $ 247万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/8513871
• 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; Genomics; 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; Immunity; Individual; Infection; Insecta; Institutes; Interferon Type I; Interferons; Investigation; Knock-out; Knockout Mice; Learning; Life; Lipopolysaccharides; Mammalian Cell; Mammals; Maps; Measures; Mediating; Medical center; Medicine; Membrane Protein Traffic; Memory; Methods; Microbe; Modeling; Molecular; Molecular Target; 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; base; combat; coping; deep sequencing; design; expression cloning; fly; gene induction; gene interaction; genetic analysis; genome sequencing; human disease; human mortality; induced pluripotent stem cell; member; mutant; new technology; pathogen; positional cloning; pressure; prevent; programs; receptor; resistance mechanism; response; screening; sensor; simulation; small molecule; sound; stem cell technology; transcription factor; viral DNA; viral RNA

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）：本申请扩展了宿主对病毒感染的抗性的成功的多方面研究。我们的方法的优势包括：1）基于诱变的无偏成分与假设驱动的成分相结合; 2）对远亲生物（小鼠和果蝇）的研究，以了解哪些防御元素是保守的; 3）拥抱新的和强大的方法来支持我们的努力。在我们迄今为止的工作中，我们已经共同确定了新的传感器（例如，LGP 2; DICER-2）激活抗病毒防御所必需的，并描绘了对病毒的反应途径，无论是在生物化学水平上还是在细胞之间的通信方面。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（SLC 15 A4; KCNJ 8/SUR 2）、转录因子（IKB; AKIRIN 2）、与膜运输或细胞器移动性有关的蛋白（AP 3B 1; STING; TR 1 M56; ATG 9A; UNC 93 B）、细胞应激（SLFN 2）、翻译后修饰（TRIM 56; TR 1 M23）和内体生理学（SLC 15 A4）。这些蛋白质中的一些是大家族的成员，可能为宿主防御的广泛新模型开辟道路。其他人强调了宿主防御中中间步骤的重要性（例如，分子在细胞内的运动）以一种以前没有考虑过的方式。每个参与小组（达拉斯、大坂和斯特拉斯堡）都有其特殊的才能，这些才能结合在一起，使我们超越了遗传学本身，融入了新技术，将加速发现宿主防御系统的基本要素。我们认识到，要理解一台机器是如何工作的，仅仅拥有一张零件清单是不够的。由于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/或与其他蛋白质相互作用以支持抗性;它们如何催化细胞内的特定反应，以及它们如何驱动或抑制基因的表达，我们认为这是一个高度动态的过程。我们认为继续进行这项研究是一个机会，可以建立一种具有既定生产力的方法：一种产生新分子、概念和试剂供整个科学界使用的方法。Poll一直并将继续在交流方法，遗传材料，最重要的是，最终来自遗传学的想法方面进行高度合作。