A Mouse Model Resource for Peroxisome Research

项目摘要 过氧化物体是代谢细胞器，是细胞信号通路的中心枢纽，具有重要的 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是因果关系 对一大群罕见的单基因疾病负责，其中一些人具有相同的危害性 等位基因可以在临床表型上表现出显著的差异，这表明存在遗传修饰物。 此外，过氧化物酶体功能障碍在一组不同的常见疾病的病理生理学中起作用。 精神错乱。尽管它们与人类健康和疾病的许多方面有关，但有限的井- 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研究。此外， 许多现有的小鼠模型已经减少，因为它们经常被放在次优的遗传背景下 或者由于生成它们的调查人员不具备 分发它们所需的基础设施，或者为了盈利而受到限制或许可费的阻碍 公司由发端研究机构发起。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 与过氧化物体生物学和引起的疾病相关的基础和翻译研究的单抗 由过氧化物酶体功能障碍引起。MPRR将是一项社区驱动的努力，利用世界领先的 具有小鼠遗传学、基因编辑和单抗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 高冲击性小鼠模型和单抗试剂。通过利用JAX遗传资源 科学库基础设施，MPRR将确保所有存放的鼠标模型都是标准化的 遗传背景以控制遗传修饰物的存在。这些菌株将作为 注解良好的资源，尽可能少的法律限制。基于社区的投入和指导 在其外部指导委员会的支持下，MPRR还将生产新的高优先级鼠标模型，并定义 标准化遗传背景上的基因类型，将它们冷冻保存，并分发给公众。 此外，MPRR还将协助对这些模型进行有针对性的表型分析，包括测量 相关的过氧化体代谢物水平。此外，基于社区的投入和外部的引导 指导委员会，MPRR将生产和宣传经验证的单抗试剂 过氧化物酶研究，包括向公众提供的相关小鼠模型的特征 如有要求，请提供。总体而言，MPRR将极大地增加可用的鼠标型号和 基于社区优先的单克隆抗体试剂和加速临床前检测的合理性 针对过氧化物酶体功能障碍引起的疾病设计了治疗干预措施。

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.