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: 10604280
• 负责人: Nancy Elise Braverman
• 金额: $ 76.06万
• 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/10604280
• 关键词: Acceleration; 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; 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 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.

项目摘要 过氧化物酶体是代谢细胞器，可作为细胞信号通路的中心枢纽，具有必不可少的 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 负责一大批稀有单基因疾病，其中一些人患有相同有害的人 等位基因可以在临床表型中显示出巨大的差异，这些临床表型表明存在遗传修饰剂。 此外，过氧化物酶体功能障碍有助于多种共同的病理生理 疾病。尽管它们与人类健康和疾病的众多方面相关，但数量有限 带注释的公开鼠标模型和研究过氧化物酶体所需的免疫资源 结构，组装和下游功能阻碍了研究社区。而且， 许多现有的鼠标模型已经减少了，因为它们经常被置于次优的遗传背景上 或不容易向公众使用，因为生成他们的调查人员没有 分配它们或以限制或许可费为营利性所需的基础架构 由原始研究机构进行的公司。在这里，我们将建立鼠标过氧化物酶体研究 杰克逊实验室（JAX）的资源（MPRR）将为鼠标模型和 与过氧化物酶体生物学和疾病有关的基础和转化研究的单克隆抗体引起的 通过过氧化物酶体功能障碍。 MPRR将是一个以社区为导向的努力，它利用世界领先 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存储库中，以加速创建，分布和正确使用 高影响小鼠模型和单克隆抗体试剂。通过利用JAX遗传资源 科学存储库基础架构，MPRR将确保所有沉积的鼠标模型都在标准化上 遗传背景以控制遗传修饰符的存在。这些菌株将作为 宣布良好的资源，其法律限制尽可能少。根据社区的投入和指导 在其外部指导委员会中，MPRR还将生产具有定义的新型高优先型鼠标模型 标准化遗传背景的基因型，冷冻保存并将其分发给公众。 此外，MPRR还将有助于这些模型的目标表型，包括测量 相关的过氧化物酶体代谢物水平。此外，基于社区的投入和外部的指导 指导委员会，MPRR将生产并宣传经过验证的单克隆抗体试剂 过氧化物酶体研究，包括表征相关的鼠标模型，可向公众提供 应要求。总体而言，MPRR将大大增加可用鼠标的数量和 基于社区驱动的优先级并加速合理临床前测试的单克隆抗体试剂 为过氧化物酶体功能障碍引起的疾病设计了治疗性干预措施。