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.

尤尼斯·肯尼迪·施赖弗国家儿童健康和人类发展研究所 (NICHD) 的智力和发育障碍 (IDD) 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、行为和转化研究。 唐氏综合症（DS；21 三体）是智力障碍最常见的遗传原因之一，每年影响美国七百名婴儿中的一名 (1, 2)，或者估计 2008 年有 -250,000 名美国人患有唐氏综合症 (3)。这种疾病是由大多数个体存在 3 个 21 号染色体拷贝引起的，除了智力障碍外，还具有多器官系统受累的特征。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主题，并且存在该疾病的小鼠模型。 细胞遗传性疾病小鼠模型存储库（Mouse Repository）于 20 世纪 70 年代开始生成和分发细胞遗传性疾病小鼠模型，特别侧重于唐氏综合症（DS；21 三体）。 DS 相关小鼠模型的创建始于 20 世纪 70 年代，并不断证明小鼠 16 号染色体片段 (Mmu16) 和人类 21 号染色体 (Hsa21) 之间的遗传同线性，这导致使用 16 三体小鼠 (Ts16) 作为 DS 相关研究的模型。 通过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 17 号染色体和 I 0（Mmu17 和 Mmu 1 0）。 许多同线染色体片段的 Pattial 三体性是在 20 世纪 80 年代根据 NICHD 的合同产生的。 其中一个被命名为 Ts65Dn 的部分三体性被证明包含大约 150 个基因，这些基因位于被认为是 Hsa21 的“唐氏综合症关键区域”。随后，根据 NICHD 合同，这些小鼠被生产并分发给 NICHD 批准接收的研究人员。 在过去的 22 年里，不同的研究人员已经生成了与 DS 相关的其他模型。 这些包括但不限于 TslCje、Ts2Cje、TslRhr、MslRhr、Tel 等。 当这些菌株和库存已提供给研究界时，中央存储库的创建确保了它们在适当的遗传背景下得到维护，并根据要求及时分发给研究人员并随后得到 NICHD 的批准。许多这些小鼠品系都处于冷冻保存状态。 2010年，NICHD重新签发了“细胞遗传性疾病小鼠模型存储库”合同，大幅增加了投资，以确保研究界能够及时获取和提高细胞遗传性疾病小鼠模型（特别是Ts65Dn）的可用性，并确保加大实验力度，修改各种品系的现有遗传背景，以提高研究人员的可用性和易用性。 2011 年发布了 RFI NOT-HD-11-002“信息请求 (RFI)：采集、处理、存储和分发人脑和其他组织以促进对唐氏综合症的理解和治疗”，大量回复认为需要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 月举办的“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 研究及倡导团体共同推进唐氏综合症患者阿尔茨海默病的诊断和治疗。本次会议参与者发现的一个弱点是现有模型系统（Ts65Dn 小鼠除外）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 已变得可用。这些菌株中的每一个都包含与 HSA21 同线的 3 个小鼠染色体区域之一的重复，其中 Dup(16)Yey 代表与人类 21 号染色体同线的最大数量的小鼠基因。