RAT21: Generation and Characterization of Rat Models of Down Syndrome

RAT21：唐氏综合症大鼠模型的生成和表征

• 批准号: 10089663
• 负责人: MICHAEL E. YEAGER
• 金额: $ 305.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-26 至 2024-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089663
• 关键词: Address; Age; Age-associated memory impairment; Anatomic Models; Anatomy; Animal Model; Basic Science; Biological; CRISPR/Cas technology; Cardiopulmonary; Cessation of life; Child; Chromosome 11; Chromosome 20; Chromosome 21; Chromosome Transfer; Chromosome abnormality; Chromosomes; Clinical Management; Complex; Congenital Abnormality; DNA Sequence; DNA sequencing; Data; Dementia; Development; Diagnosis; Disease; Down Syndrome; Elements; Functional disorder; Gene Dosage; Generations; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genotype; Germ Lines; Goals; Health; Hospitalization; Human; Human Chromosomes; Image; Immune system; Impaired cognition; Impairment; Improve Access; Incidence; Individual; Infectious Lung Disorder; Influenza A virus; Intellectual functioning disability; Learning; Learning Disabilities; Live Birth; Longevity; Mediating; Medical; Modeling; Mus; Nature; Organ; Orthologous Gene; Patients; Persons; Phenotype; Pneumonia; Population; Pre-Clinical Model; Proteomics; Publishing; Pulmonary Heart Disease; Rattus; Recurrence; Research Personnel; Resources; Respiratory Tract Infections; Severities; Systems Analysis; Techniques; Therapeutic; Tissues; Transgenic Organisms; Trisomy; Validation; atrioventricular septal defect; collaborative approach; congenital heart disorder; data warehouse; functional decline; improved; metabolomics; mortality; mouse model; multidisciplinary; neuropsychiatry; novel; novel therapeutics; pandemic disease; pre-clinical; protein expression; tool; transcriptomics; web portal; web site; zygote

Project Summary. With an incidence of one in 700-1000 live births worldwide, Down Syndrome (DS), or trisomy of human chromosome 21 (Hsa21), is the most common chromosomal abnormality. DS is most often recognized for intellectual disability, congenital malformations, and dysmorphic features, but it is also associated with seriously increased rates and severity of respiratory tract infection. To date, mice have been the dominant preclinical model species to study human DS. They have contributed greatly to our understanding of genotype- phenotype relationships in DS as well as the pathophysiology of both gene dosage and the presence of an additional chromosome. There are major challenges with regard to mouse models and DS that will be addressed in this proposal. Mouse models of DS are complex and difficult to interpret, in part because the syntenic regions of Hsa21 are split among three mouse (Mmu) chromosomes 10, 16, and 17. Consequently mice trisomic for Mmu10 or Mmu16, or Mmu17 display some features of human DS but are organ-specific, highly variable, and display phenotypes not associated with DS. In rats, the syntenic regions of Hsa21 are located on only two rat (Rno) chromosomes: 11, and 20. There are 188 Hsa21 orthologs on Rno11 and Rno20 compared to 158 Hsa21 orthologs spread over Mmu10, Mmu16, and Mmu17. Other major challenges arise because mouse models phenotypically and mechanistically fail to recapitulate the human condition with respect to key elements of cardiopulmonary pathophysiology, impairment of cognition, and development of dementia. Rat models of cardiopulmonary disease are anatomically and mechanistically closer to human forms of many diseases compared to their mouse counterparts. Our published and preliminary data from both the Human Trisome Project (HTP) and the Mouse Trisome Project (MTP) point to the urgent necessity for additional DS model species. Additionally, the complex nature of DS requires multidisciplinary and highly collaborative approaches across multiple species platforms. Thus, we propose to develop rat models of DS that can be rapidly produced, widely disseminated, act as complementary tools of biological validation for mouse models of DS, and serve as new platforms for discoveries and therapeutic opportunities in DS. DS is a complex genetic condition with significant phenotypic variability that carries high mortality rates associated with infectious lung disease, congenital heart disease, and dementia. The successful pursuit of the aims of our proposal will yield 1) powerful new rat models of DS that are phenotypically characterized on several strain backgrounds, 2) an online portal that researchers can access information, generate hypotheses, and request well-characterized trisomic rats quickly and affordably. The Rat21 resource will thus improve access to novel animal models of DS and will significantly advance preclinical and basic science studies related to DS.

项目摘要。 唐氏综合症 (DS) 或人类三体综合症，在全世界的活产儿中发病率为 700-1000 分之一 21号染色体（Hsa21）是最常见的染色体异常。 DS 最常被认可的原因是 智力障碍、先天畸形和畸形特征，但它也与 呼吸道感染的发生率和严重程度严重增加。迄今为止，老鼠一直是主要的 研究人类 DS 的临床前模型物种。他们对我们对基因型的理解做出了巨大贡献 DS 中的表型关系以及基因剂量和存在的病理生理学 额外的染色体。鼠标模型和 DS 方面存在重大挑战 本提案中提到。 DS 小鼠模型复杂且难以解释，部分原因是 Hsa21 的同线性区域被分成三个小鼠 (Mmu) 染色体 10、16 和 17。因此 Mmu10、Mmu16 或 Mmu17 三体小鼠表现出人类 DS 的一些特征，但具有器官特异性， 高度可变，并且显示与 DS 无关的表型。在大鼠中，Hsa21 的同线性区域是 仅位于两条大鼠 (Rno) 染色体上：11 和 20。Rno11 和 Rno20 上有 188 个 Hsa21 直系同源物 与分布在 Mmu10、Mmu16 和 Mmu17 上的 158 个 Hsa21 直系同源物相比。其他重大挑战出现 因为小鼠模型在表型和机制上无法重现人类的状况 尊重心肺病理生理学、认知障碍和发展的关键要素 失智。心肺疾病的大鼠模型在解剖学和机制上更接近人类模型 与小鼠相比，许多疾病的发生率更高。 我们已发布的人类三体项目 (HTP) 和小鼠三体项目的初步数据 项目（MTP）指出迫切需要额外的 DS 模式物种。此外，复杂的性质 DS 的研究需要跨多个物种平台的多学科和高度协作的方法。因此， 我们建议开发 DS 大鼠模型，该模型可以快速生产、广泛传播、充当 DS 小鼠模型的生物验证补充工具，并作为新平台 DS 的发现和治疗机会。 DS 是一种复杂的遗传病，具有显着的影响 表型变异导致与传染性肺病、先天性心脏病相关的高死亡率 疾病和痴呆症。成功实现我们提案的目标将产生 1) 强大的新大鼠模型 DS 的表型特征在多个菌株背景下，2) 研究人员可以使用的在线门户 可以快速获取信息、生成假设并请求特征明确的三体大鼠 经济实惠。因此，Rat21 资源将改善 DS 新型动物模型的获取，并将显着 推进与 DS 相关的临床前和基础科学研究。