A Mouse Model Resource for Peroxisome Research

用于过氧化物酶体研究的小鼠模型资源

• 批准号: 10334361
• 负责人: Nancy Elise Braverman
• 金额: $ 78.27万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334361
• 关键词: Address; Alleles; Antibodies; Basic Science; Biochemical; Biological; Biological Assay; Biology; Cells; Clinical; Communities; Complex; Cryopreservation; Data; Deposition; Development; Disease; Disease model; Ensure; Feedback; Fees; Free Will; Functional disorder; Generations; Genes; Genetic; Genotype; Goals; Health; Human; Hybridomas; Immunohistochemistry; Immunologics; Inbreeding; Individual; Infrastructure; Institutes; Institution; Knock-out; Knockout Mice; Knowledge; Laboratories; Laboratory Research; Legal; Licensing; Location; Measurement; Mendelian disorder; Metabolic; Methods; Mission; Modality; Modeling; Monoclonal Antibodies; Mus; Mutant Strains Mice; Organelles; Peroxisomal Disorders; Phenotype; Play; Preclinical Testing; Proteins; Reagent; Recommendation; Research; Research Personnel; Resources; Role; Science; Services; Signal Pathway; Signal Transduction; Specimen; Standardization; Structure; The Jackson Laboratory; Therapeutic Intervention; Tissues; Translational Research; United States National Institutes of Health; Universities; Western Blotting; base; base editing; body system; career; clinical phenotype; conditional knockout; cost effective; genetic resource; genome editing; improved; innovation; interest; member; model development; monoclonal antibody production; mouse genetics; mouse model; mutant; novel; outreach program; peroxisome; rational design; repository; repository infrastructure; tandem mass spectrometry; targeted treatment; therapeutic evaluation; therapy development

Project Summary Peroxisomes are metabolic organelles that serve as a central hub of cell signaling pathways and have essential roles in the normal development and functions of all human organ systems. Peroxisome dysfunction is causally responsible for a large group of rare monogenic disorders where some individuals with the same deleterious alleles can show dramatic differences in clinical phenotypes that suggest the existence of genetic modifiers. Furthermore, peroxisome dysfunction contributes to the pathophysiology of a diverse group of common disorders. Despite their relevance to numerous facets of human health and disease, the limited number of well- annotated publicly available mouse models and immunological resources required to investigate peroxisome structure, assembly, and downstream functions has hindered the research community. Moreover, the impact of many existing mouse models has been lessened since they often are placed on suboptimal genetic backgrounds or are not readily available to the public because the investigators who generated them do not have the infrastructure necessary to distribute them or are encumbered with restrictions or licensing fees to for-profit companies by the originating research institutions. Here, we will establish the Mouse Peroxisome Research Resource (MPRR) at The Jackson Laboratory (JAX) that will provide a central resource for mouse models and monoclonal antibodies for basic and translational research relevant to peroxisome biology and disorders caused by peroxisome dysfunction. The MPRR will be a community-driven effort that leverages a world-leading knowledge of mouse genetics, gene editing, and monoclonal antibody production capability as well as expertise in model development and disease model repositories to accelerate the creation, distribution, and proper use of high-impact mouse models and monoclonal antibody reagents. By leveraging the JAX Genetic Resource Sciences Repository infrastructure, the MPRR will ensure that all deposited mouse models are on standardized genetic backgrounds to control for the presence of genetic modifiers. These strains will be made available as well-annotated resources with as few legal restrictions as possible. Based on community input and the guidance of its External Steering Committee, the MPRR will also produce novel high-priority mouse models with defined genotypes on standardized genetic backgrounds, cryopreserve them, and distribute them to the public. Moreover, the MPRR will also assist in the targeted phenotyping of these models, including measurement of relevant peroxisomal metabolite levels. Furthermore, based on community input and the guidance of the External Steering Committee, the MPRR will produce and publicize validated monoclonal antibody reagents for peroxisome research, including characterizing relevant mouse models, that are made available to the public upon request. Overall, the MPRR will dramatically increase the number of available mouse models and monoclonal antibody reagents based on community-driven priority and accelerate preclinical testing of rationally designed therapeutic interventions for disorders caused by peroxisome dysfunction.

项目概要 过氧化物酶体是代谢细胞器，作为细胞信号传导途径的中心枢纽，具有重要的作用 在所有人体器官系统的正常发育和功能中发挥作用。过氧化物酶体功能障碍是导致 造成一大群罕见的单基因疾病，其中一些个体具有相同的有害物质 等位基因可以在临床表型上表现出巨大的差异，表明遗传修饰的存在。 此外，过氧化物酶体功能障碍导致多种常见疾病的病理生理学 失调。尽管它们与人类健康和疾病的许多方面相关，但健康的数量有限。 带注释的公开可用的小鼠模型和研究过氧化物酶体所需的免疫学资源 结构、组装和下游功能阻碍了研究界的发展。此外，影响 许多现有的小鼠模型已被缩小，因为它们通常被置于次优的遗传背景下 或不易向公众公开，因为生成它们的调查人员没有 分发它们所需的基础设施或受到营利性限制或许可费用的阻碍 公司由原研机构负责。在这里，我们将建立小鼠过氧化物酶体研究中心 杰克逊实验室 (JAX) 的资源 (MPRR) 将为小鼠模型和 用于与过氧化物酶体生物学及其引起的疾病相关的基础和转化研究的单克隆抗体 过氧化物酶体功能障碍。 MPRR 将是一项社区驱动的工作，利用世界领先的技术 小鼠遗传学、基因编辑和单克隆抗体生产能力的知识以及专业知识 在模型开发和疾病模型存储库中，加速创建、分发和正确使用 高影响小鼠模型和单克隆抗体试剂。利用 JAX 遗传资源 科学存储库基础设施，MPRR 将确保所有存放的小鼠模型均符合标准化 遗传背景来控制遗传修饰剂的存在。这些菌株将作为 注释良好的资源，法律限制尽可能少。基于社区的意见和指导 在其外部指导委员会的支持下，MPRR 还将生产具有明确定义的新型高优先级小鼠模型 标准化遗传背景上的基因型，冷冻保存，然后分发给公众。 此外，MPRR 还将协助这些模型的目标表型分析，包括测量 相关的过氧化物酶体代谢物水平。此外，根据社区的意见和外部的指导 指导委员会，MPRR 将生产并公布经过验证的单克隆抗体试剂 过氧化物酶体研究，包括向公众提供的相关小鼠模型的表征 根据要求。总体而言，MPRR 将显着增加可用鼠标模型的数量，并且 单克隆抗体试剂以社区为主导，合理加速临床前检测 设计了针对过氧化物酶体功能障碍引起的疾病的治疗干预措施。