REPOSITORY OF MOUSE MODELS FOR CYTOGENETIC DISORDERS

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人患有唐氏综合症(1，2)，2008年估计有25万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资料库(Mouse Repository)始于20世纪70年代，目的是产生和分发细胞遗传学紊乱的小鼠模型，特别强调唐氏综合症(DS；21三体)。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17号和I0号染色体(Mmu17和MMU L 0)上。根据NICHD的合同，许多同线染色体片段的配对三体是在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22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TslCje、Ts2Cje、TslRhr、MslRhr、TEL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。2011年发布了RFI，NOT-HD-11-002“信息请求(RFI)：人脑和其他组织的获取、处理、存储和分配，以促进对唐氏综合症的理解和治疗”，大量答复指出，需要向研究界提供更多的小鼠模型，这是一个优先问题。随后，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，阿尔茨海默病与DS研究和倡导团体联合起来，推进唐氏综合症患者阿尔茨海默病的诊断和治疗。这次会议的与会者指出的一个弱点是现有的模型系统(除Ts65Dn鼠标外)对整个研究界的可获得性有限。自那次会议以来，部分复制菌株DUP(16)YEY、OUP(L7)YEY和DUP(LO)YEY已经可用。这些菌株中的每一个都包含与HSA21共线的3个小鼠染色体区域之一的重复，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。

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, bio-behavioral, behavioral, and translational research in etiology, pathophysiology, screening, prevention, treatment, and epidemiology of these disorders. Down syndrome (DS; trisomy 21) is one ofthe 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 I 0 (Mmu17 and Mmu l 0) as well. Pattial 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 22 years, various investigators have generated other models relevant to DS. These include, but are not limited to, TslCje, Ts2Cje, TslRhr, MslRhr, Tel, 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. An RFI, NOT-HD-11-002 "Request for Information (RFI): Acquisition, Processing, Storage and Distribution of Human Brain and Other Tissues to Advance Understanding and Treatment of Down Syndrome" was released in 2011, and a substantial number of responses identified the need for increased availability of the mouse models to the research community as a priority issue. Subsequently, at a workshop "Advancing Treatment for Alzheimer Disease in Individuals with Down Syndrome" held in April, 2013, the Alzheimer disease and DS research and advocacy communities joined to advance the diagnosis and treatment of Alzheimer's disease in individuals with Down syndrome. One weakness identified by the participants in this meeting was 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, Oup( l7)Yey, and Dup(lO)Yey have become available. 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.