REPOSITORY OF MOUSE MODELS FOR CYTOGENETIC RESEARCH

用于细胞遗传学研究的小鼠模型库

基本信息

批准号：
10270129
负责人：
CATHLEEN LUTZ
金额：
$ 65万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2021-09-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10270129
关键词：
Advocacy Affect Alzheimer&apos 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 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

项目摘要

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展障碍。这计划支持生物医学，生物行为，行为和翻译病因学，病理生理学，筛查，预防，治疗和流行病学研究这些疾病。唐氏综合症（DS;三体术21）是最常见的智障遗传原因之一，每年在美国影响700名婴儿中的约1个（1、2），估计总计约250,000 2008年患有唐氏综合症的美国人（3）。由3份染色体副本引起 21在大多数人中，这种情况的特征是多器官系统参与增加智力残疾。智力障碍的分子和细胞基础由于唐氏综合症，这是一个深入研究的话题，并且存在该疾病的鼠模型。细胞遗传学疾病的小鼠模型存储库（“小鼠存储库”）始于1970年代生成和分发小鼠模型以进行细胞遗传学疾病，特别强调综合征（DS；三体症21）。与DS相关的鼠标模型的创建始于1970年代，继续证明小鼠染色体段之间的遗传同步（MMU16）和人类染色体21（HSA21），这导致将三体菌16小鼠（TS16）用作A 与DS相关的研究模型。随后小鼠和人类的遗传解剖基因组，HSA21上存在的其他基因被定位于小鼠染色体17和10（MMU17和10 MMU10）。在许多同步染色体段中产生了部分三体膜。 1980年代，根据NICHD的合同。这些局部三角体之一，被指定为TS65DN，被证明为包括大约150个基因，位于“唐氏综合症”中 HSA21的关键区域。随后，这些小鼠在NICHD下产生和分布合同，授予NICHD批准收到的调查人员。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。其中许多小鼠菌株保持在冷冻保存下。 2010年，NICHD重新发行了合同“ 细胞遗传学疾病的小鼠模型的存储库”，投资大幅增加至确保及时访问小鼠模型的细胞遗传学对研究界的疾病，尤其是TS65DN的疾病，并确保实验性增加努力修改各种菌株的现有遗传背景，以增加可用性和调查人员的易用性。在一个研讨会上，“在阿尔茨海默氏病进行治疗 2013年4月举行的唐氏综合症的人，来自阿尔茨海默氏病的参与者 DS研究与倡导社区对有限的可用性表示关注现有的模型系统（除了TS65DN鼠标以外）向整个研究社区提供了。从那以后会议，部分重复链路DUP（16）是的，dup（17）是的，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与HSA21同步的3个小鼠染色体区域之一，dup（16）代表 DS人类染色体21小鼠模型的鼠基因数量最多截至2017年，可用（4）在（请参见下图）中进行了审查。最近，TCMAC21 DS的“人性化”鼠标模型是用插入鼠标艺术中的HSA21创建的染色体（带有小鼠的丝粒和端粒） - 这是稳定传播的，因此小鼠具有大约等同于3份染色体21（2个小鼠，一个人），并共享许多人类状况的特征（5）。随着Trans-NIH的发布，包括（调查了解唐氏综合症的寿命）在2018年6月，已经有了新的兴趣支持基础科学，队列发展领域的唐氏综合症研究和临床试验。支持项目的组件1，该项目的重点是进行针对性的，高风险，高回报的基础科学研究，以了解21染色体生物学和在DS中的同时出现条件，有迫切需要确保高质量的可用性复制人类特征的条件的鼠模型。结合对 TS65DN模型对建模人类三体的局限性，重要的是新模型可将其添加到此鼠标存储库中。