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。 唐氏综合征（Down Syndrome，DS）或人类染色体三体综合征（Trisomy of human births）的发病率在全世界范围内为700-1000例活产婴儿中的1例。 21号染色体（Hsa 21）是最常见的染色体异常。DS最常被认为是 智力残疾，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。到目前为止，老鼠一直是 研究人DS的临床前模型种属。它们极大地促进了我们对基因型的理解- DS中的表型关系以及基因剂量和 额外染色体在小鼠模型和DS方面存在重大挑战， 在这个提案中。DS的小鼠模型复杂且难以解释，部分原因是 Hsa 21的同线区在三个小鼠（Mmu）染色体10、16和17中分裂。因此 Mmu 10或Mmu 16或Mmu 17的小鼠三体显示出人DS的一些特征，但具有器官特异性， 高度可变，并显示与DS无关的表型。在大鼠中，Hsa 21的同线区是 仅位于两条大鼠（Rno）染色体上：11和20。在Rno 11和Rno 20上有188个Hsa 21直向同源物 相比之下，158个Hsa 21直系同源物分布在Mmu 10、Mmu 16和Mmu 17上。其他重大挑战出现 因为小鼠模型在表型和机制上不能再现人类的状况， 关于心肺病理生理学的关键要素，认知障碍， 痴呆心肺疾病的大鼠模型在解剖学和机械学上更接近人类形式 与小鼠相比，它们对许多疾病的抵抗力更强。 我们发表的和初步的数据来自人类三体计划（HTP）和小鼠三体 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需要跨多个物种平台的多学科和高度协作的方法。因此，在本发明中， 我们建议开发DS大鼠模型，可以快速生产，广泛传播， DS小鼠模型生物学验证的补充工具，并作为 发现和治疗的机会。DS是一种复杂的遗传疾病， 表型变异携带与感染性肺病、先天性心脏病、 疾病和痴呆。成功实现我们建议的目标将产生1）强大的新大鼠模型 DS的表型特征在于几种菌株背景，2）一个在线门户网站，研究人员 可以访问信息，产生假设，并要求良好表征的三体大鼠迅速， 负担得起因此，Rat 21资源将改善对DS新型动物模型的访问，并将显著提高 推进与DS相关的临床前和基础科学研究。