A Mouse Model Resource for Peroxisome Research

项目摘要 过氧化物酶体是代谢细胞器，其充当细胞信号传导途径的中心枢纽，并具有重要的生物学功能。 在所有人体器官系统的正常发育和功能中的作用。过氧化物酶体功能障碍 负责一大群罕见的单基因疾病，其中一些人与相同的有害 等位基因在临床表型中可显示出显著的差异，这表明存在遗传修饰剂。 此外，过氧化物酶体功能障碍有助于不同类型的常见肿瘤的病理生理学。 紊乱尽管它们与人类健康和疾病的许多方面有关，但数量有限的良好- 研究过氧化物酶体所需的注释的公开可用的小鼠模型和免疫学资源 结构、组装和下游功能阻碍了研究界。此外， 许多现有的小鼠模型已经减少，因为它们经常被放置在次优的遗传背景上 或不容易向公众提供，因为产生它们的调查人员没有 基础设施，以分发它们或阻碍限制或许可费，以营利为目的 公司由原研究机构。在这里，我们将建立小鼠过氧化物酶体研究 杰克逊实验室（JAX）的资源（MPRR）将为小鼠模型和 单克隆抗体用于过氧化物酶体生物学和引起的疾病相关的基础和转化研究 过氧化物酶体功能障碍MPRR将是一个社区驱动的努力，利用世界领先的 了解小鼠遗传学、基因编辑和单克隆抗体生产能力以及专业知识 在模型开发和疾病模型库，以加快创建，分发和正确使用 高影响小鼠模型和单克隆抗体试剂。通过利用JAX遗传资源 科学库基础设施，MPRR将确保所有存放的小鼠模型都是标准化的 遗传背景，以控制遗传修饰剂的存在。这些菌株将作为 注释良好的资源，尽可能少的法律的限制。根据社区的意见和指导， 作为其外部指导委员会的一部分，MPRR还将产生具有定义的 基因型的标准化遗传背景，冷冻保存，并分发给公众。 此外，MPRR还将有助于这些模型的靶向表型分析，包括测量 相关过氧化物酶体代谢物水平。此外，根据社区的投入和外部的指导， 指导委员会，MPRR将生产和宣传经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特征 应要求总的来说，MPRR将大大增加可用小鼠模型的数量， 单克隆抗体试剂基于社区驱动的优先权，合理加速临床前试验 为过氧化物酶体功能障碍引起的疾病设计治疗干预措施。

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.