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Principal Investigator: Eugene Yu
Organization: ROSWELL PARK CANCER INSTITUTE CORP
Fiscal Year: 2024
Award: $450,011
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
ABSTRACT
The presence of an extra copy of human chromosome 21 (trisomy 21) is associated with Down syndrome (DS),
and this is the most common live-born chromosomal alteration in humans. In the United States, DS has an
incidence rate of approximately 1 in 691 newborns, and individuals with DS exhibit many clinical phenotypes;
nervous system involvement is among the most burdensome. Today, human trisomy 21 remains a leading
genetic cause of developmental delays and intellectual disabilities with near universal penetrance. Effective
treatments for such clinical manifestations would be transformative because these treatments could profoundly
improve the quality of life for individuals with DS. Based on the prevailing hypothesis that particular phenotypes
of DS are affected by the dosage increase of specific genes on human chromosome 21 (Hsa21), triplications of
particular genomic segments, i.e., human segmental trisomies, have been studied in detail to establish
genotype–phenotype relationships with the ultimate goal of identifying dosage sensitive causative genes that
can serve as therapeutic targets. However, such efforts have been severely hampered by the lack of an adequate
number of informative segmental trisomy cases. Fortunately, amore fruitful alternative based on the evolutionary
conservation between humans and mice has also been pursued, and this approach has allowed the genetic
dissection efforts to advance much more rapidly. For example, analyses of the DYRK1A gene ortholog in mice
demonstrated that this gene is a causative determinant for DS-associated developmental cognitive deficits;
subsequently, these results served as the basis for the only successful clinical trials involving developmental
cognitive deficits and orthologous Hsa21 genes. To further the genetic dissection efforts, we have developed a
large number of mouse mutants carrying different chromosomal rearrangements in Hsa21 orthologous regions.
In Aim 1 of this application, we will utilize these mouse mutants and develop new mutants by using CRISPR -
mediated genome engineering to enhance our efforts to identify novel dosage sensitive causative genes
underlying developmental cognitive deficits in DS, whose human orthologs can serve as therapeutic targets
along with the DYRK1A gene. Besides acting through a gene dosage increase, human trisomy 21 may have
other ways of influencing phenotypes, such as by altering the nuclear architecture and thus gene expression. In
Aim 2 of this application, we will test this second hypothesis by using mouse models. We believe the success of
our proposed project will have a transformative impact on research on DS in general and on DS-associated
developmental cognitive deficits in particular.
Terms: <0-4 weeks old><3-D><3-Dimensional><3D><Aberrant Chromosome><Affect><Animals><Architecture><Bartholin-Patau syndrome><CRISPR><CRISPR/Cas system><Candidate Disease Gene><Candidate Gene><Cell Body><Cells><Cerebral cortex><Characteristics><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosomal Rearrangement><Chromosome 16><Chromosome 21><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome abnormality><Chromosomes><Clinical><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Cognitive deficits><Consensus><Cytogenetic Aberrations><Cytogenetic Abnormalities><Data><Development><Developmental Delay><Developmental Delay Disorders><Dissection><Down's Syndrome><Edward's syndrome><Edwards syndrome><Engineering><Engineering / Architecture><Exhibits><Gene Copy Number><Gene Dosage><Gene Expression><Generations><Genes><Genetic><Genetic analyses><Genome><Genome engineering><Genomic Segment><Genotype><Goals><Human><Human Chromosomes><IFNAR><IFNAR1><IFNAR1 gene><Incidence><Individual><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Interferon Receptor><Investments><Langdon Down syndrome><Live Birth><Maps><Mediating><Medical><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mongolism><Murine><Mus><Mutant Strains Mice><Nervous System><Neurologic Body System><Neurologic Organ System><Newborn Infant><Newborns><Nuclear><Ortholog><Orthologous Gene><Outcome><PARK20><Patau syndrome><Patau's syndrome><Penetrance><Persons><Phenotype><Play><Process><QOL><Quality of life><Reporting><Research><Role><SYNJ1><SYNJ1 gene><Specific Child Development Disorders><Technology><Testing><Therapeutic><Trisomy><Trisomy 13><Trisomy 13 Syndrome><Trisomy 18><Trisomy 18 Syndrome><Trisomy 21><Ts65Dn><United States><chromosomal defect><chromosome 13 trisomy><chromosome 13 trisomy syndrome><chromosome 18 trisomy><chromosome 21 trisomy syndrome><chromosome defect><clinical phenotype><cognitive ability><cognitive defects><cognitive enhancement><cognitive function><congenital acromicria syndrome><developmental><discover genes><dosage><effective therapy><effective treatment><gene discovery><genetic analysis><genome segment><genomic region><improved><inhibitor><innovate><innovation><innovative><intellectual and developmental disability><limited intellectual functioning><morbus Down><mouse Ts65Dn><mouse model><mouse mutant><murine model><mutant><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><newborn child><newborn children><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pseudohypertrophic progressive muscular dystrophy><segregation><social role><success><synaptojanin><synaptojanin-1><synaptojanin1><therapeutic target><three dimensional><trisomy 21 syndrome>