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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.

尤尼斯·肯尼迪·施莱弗国家智障和发展性残疾分会