REPOSITORY OF MOUSE MODELS FOR CYTOGENETIC DISORDERS

尤尼斯·肯尼迪·施莱佛国家儿童健康和人类发展研究所智力和发育残疾分支赞助旨在预防和改善智力和发育残疾的研究和研究培训。该计划支持这些疾病的病因学，病理生理学，筛查，预防，治疗和流行病学的生物医学，生物行为，行为和转化研究。 唐氏综合征（DS; 21三体）是智力残疾最常见的遗传原因之一，每年影响美国700名婴儿中的1名（1，2），或2008年估计共有约250，000名美国人患有唐氏综合症（3）。由于大多数个体中存在21号染色体的3个拷贝，这种情况的特征是除了智力残疾之外还涉及多个器官系统。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，并且存在该疾病的小鼠模型。 细胞遗传学疾病小鼠模型库（Mouse Repository）始于20世纪70年代，用于生成和分发细胞遗传学疾病的小鼠模型，特别强调唐氏综合征（DS; 21三体）。 与DS相关的小鼠模型的创建始于20世纪70年代，并随着小鼠16号染色体（Mmu 16）和人类21号染色体（Hsa 21）之间的遗传同线性的证明而继续，这导致使用16三体小鼠（Ts16）作为DS相关研究的模型。 随着随后对小鼠和人类基因组的遗传解剖，Hsa21上存在的其他基因也定位于小鼠染色体17和10（Mmu 17和Mmu 10）。 在20世纪80年代，根据与NICHD的合同，产生了许多同线染色体片段的Pattial三体。 这些部分三体之一，命名为Ts65Dn，被证明包括大约150个基因，位于被认为是Hsa21的"唐氏综合征关键区域"。随后，根据NICHD合同，这些小鼠被生产并分发给NICHD批准接收它们的研究者。 在过去的22年里，各种研究人员已经产生了其他相关的DS模型。 这些包括但不限于TslCje、Ts2Cje、TslRhr、MslRhr、Tel等。 在向研究界提供这些菌株和种群后，建立一个中央储存库确保了它们保持适当的遗传背景，并确保了在调查人员提出要求时及时将其分发给调查人员，并在得到国家排雷中心的批准后分发给他们。这些小鼠品系中的许多在冷冻保存下维持。2010年，NICHD重新发布了"细胞遗传学疾病小鼠模型库"合同，大幅增加了投资，以确保研究界及时获得并增加细胞遗传学疾病小鼠模型的可用性，特别是Ts65Dn，并确保增加实验努力，以修改各种菌株的现有遗传背景，investigators. 2011年发布了一份RFI，即NOT-HD-11 - 002 "信息请求（RFI）：人类大脑和其他组织的获取、处理、存储和分配，以促进对唐氏综合征的理解和治疗"，大量的回复将增加小鼠模型对研究界的可用性作为优先问题。 随后，在2013年4月举行的“推进唐氏综合症患者阿尔茨海默病治疗”研讨会上，阿尔茨海默病和DS研究和宣传界加入了推进唐氏综合症患者阿尔茨海默病的诊断和治疗。与会者在这次会议上发现的一个弱点是，现有的模型系统（除了Ts65Dn小鼠）对整个研究界的可用性有限。自那次会议以来，部分重复菌株Dup（16）Yey、Oup（17）Yey和Dup（10）Yey已经可用。这些菌株中的每一个都含有与HSA 21同线的3个小鼠染色体区域之一的重复，其中Dup（16）Yey代表与人染色体21同线的最大数量的鼠基因。

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.