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: 10683920
• 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 2023-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683920
• 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; Individual; Intellectual functioning disability; Investigation; Investments; Longevity; Maintenance; Methods; Modeling; Molecular; Mouse Strains; Mus; National Institute of Child Health and Human Development; PPBP gene; Participant; Prevention; Procedures; Production; Research; Research Personnel; Research Training; Resources; Study models; Synteny; Time; 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; pregnant; prenatal; preservation; prevent; programs; repository; screening; telomere; trait

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.

Eunice Kennedy Shriver National的智力和发展障碍（IDD）分支机构 儿童健康与人类发展研究所（NICHD）赞助研究与研究培训 旨在防止和改善智力和发育障碍。该计划支持这些疾病的病因，病理生理学，筛查，预防，治疗和流行病学的生物医学，生物行为，行为和转化研究。 唐氏综合症（DS;三体术21）是智障最常见的遗传原因之一，每年影响700名婴儿中〜1个婴儿（1，2），估计总计约250,000 2008年患有唐氏综合症的美国人（3）。在大多数个体中存在3个染色体的3份副本引起的，此情况的特征是多器官系统的参与，除了智力障碍。唐氏综合症引起的智力障碍的分子和细胞基础一直是深入研究的话题，并且存在该疾病的鼠模型。 细胞遗传学疾病的小鼠模型的存储库（“小鼠存储库”）始于1970年代，以生成和分发小鼠模型以进行细胞遗传学疾病，并特别强调唐氏综合症（DS； Trisomy 21）。与DS相关的小鼠模型的创建始于1970年代，并继续证明了小鼠染色体16（MMU16）和人类染色体21（HSA21）之间的遗传同步，从而导致了三体术16小鼠（TS16）作为与DS相关的研究模型。随后小鼠和人类基因组的遗传解剖，HSA21上存在的其他基因也位于小鼠染色体17和10（MMU17和MMU10）中。根据与NICHD的合同，在1980年代生成了许多同时染色体的部分三体。这些局部三晶中的一个被指定为TS65DN，其中包括位于HSA21的“唐氏综合症关键区域”中的大约150个基因。随后，这些小鼠是根据NICHD合同生产和分配给NICHD批准收到的调查人员的。 在过去的30年中，各种研究人员生成了与DS相关的其他模型。这些 包括但不限于TS1CJE，TS2CJE，TS1RHR，MS1RHR，TC1等。当这些 菌株和股票已向研究社区提供，这是一个中央的创建 存储库确保了他们对适当的遗传背景的维护 根据NICHD的批准，应及时向调查人员分发向调查人员分发。 这些小鼠菌株中的许多都保持在冷冻保存下。在2010年，NICHD重新发布了“细胞遗传疾病的老鼠模型的存储库”，其投资大幅增加，以确保及时访问和增加小鼠模型的细胞遗传学疾病模型，尤其是TS65DN，对研究社区，并确保增加实验背景，以增加现有遗传的可用性，以使各种使用者更适合使用调查者，并可以通过调查人员使用良好的使用。在2013年4月举行的“阿尔茨海默氏病在患有唐氏综合症患者中的阿尔茨海默氏病的治疗”的研讨会上，来自阿尔茨海默氏病和DS研究与倡导社区的参与者对现有模型系统（除TS65DN小鼠）的现有模型系统的有限可用性表示关注。自从那次会议以来，部分重复链接dup（16）yey，dup（17）yey和dup（10）已成为 可用，现在是该鼠标存储库的一部分。这些菌株中的每一个都包含重复 在3个与HSA21同步的3个小鼠染色体区域之一中，DUP（16）代表了2017年截至2017年的DS的21个小鼠模型的鼠基因最多的鼠基因，并在（4）中进行了综述，并参见下图。最近，已经在小鼠人造染色体中插入HSA21的TCMAC21“人源化”小鼠模型（带有小鼠的中心粒和端粒） - 该小鼠的传播稳定，因此大约具有3份染色体的3副拷贝21（2小鼠，一个人，一个人），并具有许多人的条件（5）。随着Trans-NIH的推出包括（研究整个生命周期的共同存在状况，以了解唐氏综合症的项目），2018年6月，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产生了重新兴趣。为了支持该项目的组成部分，该项目的重点是进行有针对性的，高风险的高回报基础科学研究，以了解DS中的21个生物学染色体和同时发生的条件，因此有必要确保对复制人类特征的疾病的高质量鼠模型的利用。再加上对TS65DN模型对建模人类三体的局限性的担忧，重要的是要将新模型添加到该小鼠存储库中。