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Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits

Award Number: R01HD109750
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $449,608 )
2026	2026	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Child Health and Human Development Extramural Research	000	5	9/3/2026	NON-COMPETING CONTINUATION	$449,608
														Subtotal = $449,608

Issue Date FY: 2025 ( Subtotal = $565,641 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Child Health and Human Development Extramural Research	000	4	8/20/2025	NON-COMPETING CONTINUATION	$449,608
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Child Health and Human Development Extramural Research	001	4	9/11/2025	SUPPLEMENT FOR EXPANSION	$116,033
														Subtotal = $565,641

Issue Date FY: 2024 ( Subtotal = $892,259 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Child Health and Human Development Extramural Research	000	3	8/27/2024	NON-COMPETING CONTINUATION	$450,011
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Child Health and Human Development Extramural Research	001	3	8/28/2024	SUPPLEMENT FOR EXPANSION	$442,248
														Subtotal = $892,259

Issue Date FY: 2023 ( Subtotal = $898,642 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Child Health and Human Development Extramural Research	000	2	8/16/2023	NON-COMPETING CONTINUATION	$460,655
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Child Health and Human Development Extramural Research	001	2	8/30/2023	SUPPLEMENT FOR EXPANSION	$437,987
														Subtotal = $898,642

Issue Date FY: 2022 ( Subtotal = $475,839 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Child Health and Human Development Extramural Research	001	1	9/15/2022	NEW	$14,535
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Child Health and Human Development Extramural Research	000	1	9/13/2022	NEW	$461,304
														Subtotal = $475,839

Grand Total All Awards = $3,281,989

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Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits

Award Number: R01HD109750

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/13/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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