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

基本信息

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
项目类别：
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

项目摘要

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。全球700-1000个活产的发生率是唐氏综合症（DS）或人类三体性的发生率染色体21（HSA21）是最常见的染色体异常。 DS通常被认可智力残疾，先天性畸形和畸形特征，但也与严重增加了呼吸道感染的速度和严重程度。迄今为止，老鼠一直是主要的临床前模型研究人类DS。他们为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的病理生理学和存在其他染色体。在鼠标模型和DS方面存在主要挑战在此提案中解决。 DS的鼠标模型很复杂且难以解释，部分是因为 HSA21的同义区域分为三种小鼠（MMU）染色体10、16和17。 MMU10或MMU16或MMU17的小鼠三异构体显示人类DS的某些特征，但是器官特异性的，高度可变，并且显示与DS无关的表型。在大鼠中，HSA21的同义区域为仅位于两只大鼠（RNO）染色体上：11和20。相比之下，与MMU10，MMU16和MMU17相比158 HSA21直系同源物。出现其他主要挑战因为小鼠模型在表型和机械上无法用尊重心肺病理生理学的关键要素，认知障碍和发展失智。心肺疾病的大鼠模型在解剖学和机械上更接近人类形式与小鼠相比，许多疾病。我们从人类Trisome项目（HTP）和Mouse Trisome发表的发布和初步数据项目（MTP）指出了其他DS模型物种的迫切需要。此外，复杂的性质 DS需要多个物种平台上的多学科和高度协作的方法。因此，我们建议开发可快速生产，广泛传播的DS的大鼠模型，充当 DS鼠标模型的生物学验证的互补工具，并作为新平台 DS的发现和治疗机会。 DS是一个复杂的遗传条件具有高死亡率的表型变异性与感染性肺部疾病，先天性心脏疾病和痴呆症。对我们提案的目标的成功追求将产生1）强大的新老鼠模型在几种应变背景上表征表征的DS，2）研究人员的在线门户网站可以访问信息，产生假设，并请求迅速和负担得起。因此，Rat21资源将改善对DS新型动物模型的访问与DS相关的临床前和基础科学研究。