NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
Down syndrome (trisomy 21) is one of the most common genetic causes of intellectual disability, affecting ~5,700 babies born in the U.S. each year (1, 2), or an estimated total of ~250,000 Americans living with DS 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 DS have been a topic of intensive study, and murine models of the condition have been developed for the research community studying DS. This specific acquisition, now called the Repository of Mouse Models for Down Syndrome, (“Mouse Repository”) began in the 1970s to generate and distribute mouse models with cytogenetic disorders, with special emphasis on DS. The demonstration of genetic synteny between a segment of mouse chromosome 16 (Mmu16) and human chromosome 21 (Hsa21) 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 10 (Mmu17 and Mmu10) as well. Partial trisomies for a number of syntenic chromosomal segments were generated in the 1980s, under contract to NICHD. One of these partial trisomy models, designated Ts65Dn, includes approximately 150 genes located in what is considered the “Down syndrome critical region” of Hsa21, but it also includes non-orthologous genetic material from Mmu17, which may adversely impact the utility of this model to replicate human phenotypes, particularly with regard to neurologic function (4). During the last 30 years, various investigators have generated other models relevant to DS. These include, but are not limited to, Ts1Cje, Ts2Cje, Ts1Rhr, Ms1Rhr, Tc1, Dp16, TcMAC21, Ts66Yah, and others. The partial duplication strains Dup(16)Yey, Dup(17)Yey, and Dup(10)Yey have become available and are now part of this Mouse Repository. 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. Mouse models for DS available as of 2017 are reviewed in (reference 5; see Figure below). Several years ago, the TcMAC21 “humanized” mouse model of DS was created with Hsa21 inserted in a mouse artificial chromosome (with mouse centromere and telomere)—this is stably transmitted so mice have approximately the equivalent of 3 copies of chromosome 21 (2 mouse, one human), and share many features of the human condition (6). Even more recently, the Ts66Yah model was generated by CRISPR/Cas9, to address concerns about the Ts65Dn model construct validity—this model eliminates the genomic regions unrelated to Hsa21 on the minichromosome (7). In addition, the NIH-wide INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project (https://www.nih.gov/include-project) was launched in June 2018 to support basic, clinical, and translational research in Down syndrome. To support component 1 of the project, which is focused on conducting targeted, high-risk, high-reward basic science studies to understand chromosome 21 biology and the co-occurring conditions in DS, there is a pressing need to ensure the availability of high-quality murine models of the condition that replicate human traits. A repository of murine models for DS has been a valuable resource for investigators interested in studying genetic, molecular, and cellular mechanisms that underlie various aspects of DS, including cognitive impairment, heart defects, and many other co-occurring conditions attributed to the presence of an extra copy of chromosome 21. Since many of these mice are difficult to breed and propagate, the federal government has contracted with a vendor of murine model organisms to make them available to the research community. Combined with concerns about the Ts65Dn model’s limitations with regard to modeling the human trisomy and poor breeding abilities, there has been an emphasis on bringing new models into this Mouse Repository. When these strains and stocks have been made available to the research community, this central repository has ensured their maintenance on appropriate genetic backgrounds and their distribution to investigators upon request in a timely manner. Indeed, during the past 5 years of this contract (beginning in 2020), two recently developed models of DS, the TcMAC21 (6) and Ts66Yah (7) strains, have been added to this resource. They are proving to be popular with investigators and may ultimately be more valuable to the research community for some purposes than some of the older strains. However, the TcMAC21 strain has recently raised concerns about the later presentation of a lethal adult phenotype in some animals that was not consistent with adult phenotypes in humans with the condition and had not been previously described. Nonetheless, the diversity of strains available in the resource is essential for the community because no single strain replicates the human condition perfectly, and each strain has its relative merits and shortcomings.
Up to $650K
2026-09-21
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