REPOSITORY OF MOUSE MODELS FOR CYTOGENETIC DISORDERS

细胞遗传学疾病小鼠模型库

• 批准号: 9153266
• 负责人: CATHLEEN LUTZ
• 金额: $ 64.73万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-22 至 2016-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9153266
• 关键词: Advocacy; Affect; Alzheimer' s Disease; American; Aneuploidy; Behavioral; Biological Models; Brain; Child; Child health care; Chromosomes; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 21; Communities; Contracts; Cryopreservation; Cytogenetics; Diagnosis; Disease; Disease model; Dissection; Down Syndrome; Educational workshop; Ensure; Epidemiology; Etiology; Functional disorder; Genes; Genetic; Human; Human Chromosomes; Human Development; Human Genome; Individual; Institutes; Intellectual functioning disability; Investments; Life; Maintenance; Modeling; Molecular; Mouse Strains; Mus; National Institute of Child Health and Human Development; Participant; Prevention; Process; Research; Research Personnel; Research Training; Study models; Synteny; Tissues; Translational Research; Trisomy; base; body system; meetings; mouse Trisomy 16; mouse Ts65Dn; mouse genome; mouse model; prevent; programs; repository; response; screening

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.

Eunice Kennedy Shriver国家儿童健康与人类发展研究所（NICHD）赞助研究与研究培训的智力和发育障碍（IDD）分支，旨在预防和改善知识和发展障碍。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;三体疾病21）是智障最常见的遗传原因之一，每年影响美国700名婴儿中有1个（1，2），或者估计为2008年唐氏综合症患有唐氏综合症的美国人总数为-25万美国人（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（小鼠存储库）的小鼠模型的存储库始于1970年代，以生成和分发小鼠模型以进行细胞遗传学疾病，并特别强调了唐氏综合症（DS; Trisome 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，从而导致使用了三体性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I 0（MMU17和MMU L 0）中。 根据与NICHD的合同，在1980年代生成了许多同时染色体片段的patial trisomies。 这些局部三体菌中的一个被指定为TS65DN，被证明包括位于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22年中，各种研究人员生成了与DS相关的其他模型。 其中包括但不限于TSLCJE，TS2CJE，TSLRHR，MSLRHR，TEL等。 当这些菌株和股票已向研究社区提供时，中央存储库的创建确保了他们对适当的遗传背景的维护，并根据要求及时地要求将其分配给调查人员，并在NICHD批准之后进行。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“细胞遗传学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，并确保增加实验性企业以增加现有遗传的可用性，从而使各种可用性的使用量更高，以通过调查器来调查。 RFI，NOT-HD-11-002“信息请求（RFI）：收购，处理，存储和分布人脑和其他组织以提高对唐氏综合症的理解和治疗”，并于2011年发布，大量响应确定了将小鼠模型增加对研究社区的优先问题的需求。 随后，在2013年4月举行的“阿尔茨海默氏病的治疗中，阿尔茨海默氏病的治疗”在阿尔茨海默氏病和DS研究与倡导群落中加入了唐氏综合症患者的阿尔茨海默氏病的诊断和治疗。参与者在这次会议上发现的一个弱点是对整个研究社区的现有模型系统（TS65DN鼠标除外）的可用性有限。自那次会议以来，部分重复脉动dup（16）yey，oup（l7）yey和dup（lo）yey已获得。这些菌株中的每一个都包含与HSA21同步的3个小鼠染色体区域之一的重复，而DUP（16）代表与人类21染色体同步的鼠基因数量最多。