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.

R24HD105357

2020-09-26

2024-09-25