REPOSITORY OF MOUSE MODELS FOR CYTOGENETIC RESEARCH

用于细胞遗传学研究的小鼠模型库

• 批准号: 10928687
• 负责人: CATHLEEN LUTZ
• 金额: $ 65万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-22 至 2024-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10928687
• 关键词: Advocacy; Affect; Alzheimer' s Disease; American; Aneuploidy; Animal Model; Artificial Chromosomes; Basic Science; Behavioral Research; Biological Models; Biology; Breeding; Centromere; Chromosome 16; Chromosome 21; Chromosomes; Clinical Trials; Communities; Contractor; Contracts; Cryopreservation; Cytogenetics; Development; Disease; Disease model; Dissection; Down Syndrome; Educational workshop; Embryo; Ensure; Epidemiology; Etiology; Female; Fertility; Functional disorder; Genes; Genetic; Germ Cells; Human; Human Chromosomes; Human Genome; Implant; Individual; Intellectual functioning disability; Investigation; Investments; Late Onset Alzheimer Disease; Longevity; Maintenance; Methods; Modeling; Molecular; Mouse Strains; Mus; National Institute of Child Health and Human Development; PPBP gene; Participant; Prevention; Procedures; Production; Qualifying; Research; Research Personnel; Research Training; Resources; Study models; Synteny; Translational Research; Trisomy; United States National Institutes of Health; base; biobehavior; body system; cohort; community engaged research; embryo cryopreservation; high reward; high risk; human model; humanized mouse; interest; male; meetings; mouse Trisomy 16; mouse Ts65Dn; mouse genome; mouse model; prenatal; preservation; prevent; programs; repository; screening; telomere; trait; transmission process

The Intellectual and Developmental Disabilities (IDD) Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) sponsors research and research training aimed at preventing and ameliorating intellectual and developmental disabilities. The program supports , biomedical, biobehavioral, behavioral, and translational research in etiology, pathophysiology, screening, prevention, treatment, and epidemiology of these disorders. Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, affecting ~1 in 700 babies in the U.S. each year (1, 2), or an estimated total of ~250,000 Americans living with Down syndrome in 2008 (3). Caused by the presence of 3 copies of chromosome 21 in most individuals, this condition is characterized by multiple organ system involvement in addition to intellectual disability. The molecular and cellular bases of intellectual disability due to Down syndrome have been a topic of intensive study, and murine models of the disease exist. The Repository of Mouse Models for Cytogenetic Disorders (“Mouse Repository”) began in the 1970s to generate and distribute mouse models for cytogenetic disorders, with special emphasis on Down syndrome (DS; trisomy 21). The creation of mouse models relevant to DS began in the 1970s and continued with the demonstration of genetic synteny between a segment of mouse chromosome 16 (Mmu16) and human chromosome 21 (Hsa21), which led to the use of the trisomy 16 mouse (Ts16) as a model for studies relevant to DS. With the subsequent genetic dissection of both mouse and human genomes, other genes present on Hsa21 were localized to mouse chromosomes 17 and 10 (Mmu17 and Mmu10) as well. Partial trisomies for a number of syntenic chromosomal segments were generated in the 1980s, under contract to NICHD. One of these partial trisomies, designated Ts65Dn, proved to include approximately 150 genes located in what is considered the “Down syndrome critical region” of Hsa21. Subsequently, these mice were produced and distributed, under an NICHD contract, to investigators approved for receipt of them by NICHD. During the last 30 years, various investigators have generated other models relevant to DS. These include, but are not limited to, Ts1Cje, Ts2Cje, Ts1Rhr, Ms1Rhr, Tc1, and others. When these strains and stocks have been made available to the research community, the creation of a central repository has ensured their maintenance on appropriate genetic backgrounds and their distribution to investigators upon request in a timely manner and subsequent to approval by NICHD. Many of these mouse strains are maintained under cryopreservation. In 2010, the NICHD reissued the contract “A Repository of Mouse Models of Cytogenetic Disorders” with a substantial increase in investment to ensure timely access to and increased availability of mouse models for cytogenetic disorders, particularly Ts65Dn, to the research community, and to ensure increased experimental efforts to modify the existing genetic backgrounds for the various strains to increase availability and ease of use by investigators. At a workshop “Advancing Treatment for Alzheimer Disease in Individuals with Down Syndrome” held in April, 2013, the participants from the Alzheimer disease and DS research and advocacy communities expressed concern with the limited availability of existing model systems (other than the Ts65Dn mouse) to the research community at large. Since that meeting, the partial duplication strains Dup(16)Yey, Dup(17)Yey, and Dup(10)Yey have become available and are now part of this Mouse Repository. Each of these strains contains a duplication of one of the 3 mouse chromosome regions that are syntenic to HSA21, with Dup(16)Yey representing the largest number of murine genes syntenic to the human chromosome 21 Mouse models for DS available as of 2017 are reviewed in (4) and see Figure below. More recently, the TcMAC21 “humanized” mouse model of DS has been created with Hsa21 inserted in a mouse artificial chromosome (with mouse centromere and telomere)—this is stably transmitted so mice have approximately the equivalent of 3 copies of chromosome 21 (2 mouse, one human), and share many features of the human condition (5). With the launch of the trans-NIH INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) project in June 2018, there has been a renewed interest in supporting Down syndrome research in the domains of basic science, cohort development, and clinical trials. To support component 1 of the project, which is focused on conducting targeted, high- risk, high-reward basic science studies to understand chromosome 21 biology and the co-occurring conditions in DS, there is a pressing need to ensure the availability of high-quality murine models of the condition that replicate human traits. Combined with concerns about the Ts65Dn model’s limitations with regard to modeling the human trisomy, it is important that new model(s) be added to this Mouse Repository.

尤尼斯·肯尼迪·施莱弗国家儿童健康和人类发展研究所的智力和发育障碍分会赞助旨在预防和改善智力和发育障碍的研究和研究培训。该计划支持这些疾病的病因学、病理生理学、筛查、预防、治疗和流行病学方面的生物医学、生物行为、行为和翻译研究。 唐氏综合症(DS；21三体)是导致智力残疾的最常见的遗传原因之一，每年在美国每700名婴儿中就有1人受到影响(1，2)，即2008年估计有约250,000美国人患有唐氏综合症(3)。这种疾病是由21号染色体的3个拷贝在大多数个体身上引起的，除了智力障碍外，还具有多器官系统受累的特点。唐氏综合征所致智力障碍的分子和细胞基础一直是深入研究的主题，并且存在这种疾病的小鼠模型。 小鼠细胞遗传学疾病模型储存库(“小鼠储存库”)始于20世纪70年代，以唐氏综合症(DS；21三体)为重点，建立和分发小鼠细胞遗传学疾病模型。与DS相关的小鼠模型的建立始于20世纪70年代，随后证明了小鼠16号染色体(Mmu16)和人类21号染色体(Hsa21)之间的遗传同步性，这导致了16三体小鼠(TS16)作为与DS相关的研究模型的使用。随着随后对小鼠和人类基因组的遗传解剖，Hsa21上的其他基因也被定位在小鼠的17和10号染色体(Mmu17和Mmu10)上。根据NICHD的合同，一些同线染色体片段的部分三体是在20世纪80年代产生的。这些部分三体中的一个被命名为Ts65Dn，被证明包括大约150个基因，位于Hsa21的“唐氏综合症临界区”。随后，根据NICHD的合同，这些小鼠被生产并分发给NICHD批准接收它们的调查人员。 在过去的30年里，不同的研究人员建立了其他与DS相关的模型。这些包括但不限于Ts1Cje、Ts2Cje、Ts1Rhr、Ms1Rhr、Tc1等。当这些菌株和种群提供给研究界时，中央储存库的建立确保了它们在适当的遗传背景下保持不变，并在提出请求并得到NICHD批准后及时分发给调查人员。 这些小鼠品系中的许多都被保存在超低温保存中。2010年，NICHD重新发布了“细胞遗传学疾病小鼠模型资料库”合同，大幅增加了投资，以确保研究界及时获得和增加细胞遗传学疾病小鼠模型，特别是Ts65Dn，并确保加强实验工作，修改各种菌株的现有遗传背景，以增加研究人员的可得性和易用性。在2013年4月举行的“唐氏综合症患者阿尔茨海默病的先进治疗”研讨会上，来自阿尔茨海默病和DS研究和倡导社区的参与者表达了对现有模型系统(Ts65Dn小鼠除外)对整个研究界可用的有限的关注。自那次会议以来，部分复制品系DUP(16)YEY、DUP(17)YEY和DUP(10)YEY已经可用，现在是该小鼠储存库的一部分。这些菌株中的每一个都包含与HSA21同线的3个小鼠染色体区域之一的重复，其中DUP(16)Yey代表与人类21号染色体共线的最大数量的小鼠基因，(4)中回顾了截至2017年可用的DS小鼠模型，见下图。最近，TcMAC21“人源化”的DS小鼠模型已经被创造出来，将Hsa21插入到小鼠的人工染色体中(带有小鼠着丝粒和端粒)--这是稳定传播的，因此小鼠大约相当于21号染色体的3个拷贝(2只小鼠，1个人)，并具有人类条件的许多特征(5)。随着2018年6月跨NIH Include(了解唐氏综合症的共生条件调查)项目的启动，人们对支持基础科学、队列发展和临床试验领域的唐氏综合症研究重新产生了兴趣。为了支持该项目的组成部分1，该项目的重点是进行有针对性的、高风险、高回报的基础科学研究，以了解21号染色体生物学和DS的共生条件，迫切需要确保提供复制人类特征的高质量小鼠模型。结合对Ts65Dn模型在模拟人类三体方面的局限性的担忧，重要的是将新模型(S)添加到这个鼠库中。