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New Down syndrome mouse models to understand development of sex-specific co-occurring phenotypes

Award Number: R24OD039898
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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New Down syndrome mouse models to understand development of sex-specific co-occurring phenotypes - SUMMARY Trisomy 21 (Ts21) leads to phenotypes collectively known as Down syndrome (DS). Males and females with Ts21 differ in the incidence and severity of many traits associated with DS. Sex-specific traits caused by Ts21 are not well understood because of experimentation with small sample sizes, non-segregation of data from males and females, and a historical usage of male mice in preclinical DS mouse models. Because of differences in how phenotypes are manifest in males and females, treatment of some sex-specific deficiencies in individuals with DS may need to take a separate course or begin at different times. Sexual dimorphisms in DS preclinical models are becoming increasingly recognized but are still not well characterized, limiting the translational value of the models. Many of the sexually dimorphic traits begin before puberty and the biological sources of those developmental differences—either from gonadal secretions or sex chromosome gene expression—are unknown. Additionally, a systematic longitudinal analysis of hormone levels and their relationship to the development of sex-specific trait differences in DS mouse models has not been done. There is no current model to understand developmental mechanisms of sex-related differences in DS phenotypes. The four core genotype (FCG) mouse model separates the independent influences of gonadal sex from sex chromosomal complement and provides a means to delineate how and from what sources sex-specific phenotypes arise in DS. The objective of this project is to create the first ever systematic determination of the sources of sex differences in DS phenotypes using the offspring from Dp16 x FCG matings. These Dp16 x FCG matings produce eight groups of mice that vary in their components of triplicated genes, gonadal sex, and sex chromosomes, allowing the decoupling of the influence of gonadal sex and sex chromosomes on development of sexually dimorphic phenotypes involved in DS. To establish the validity of this novel preclinical model for researchers investigating sex-specific traits in DS, this project will quantify: 1) essential background traits including growth and developmental milestones; 2) a longitudinal analysis of hormone and hormone receptors; 3) in vivo PET/CT brain metabolic network covariance mapping, along with ex vivo high-resolution MRI brain regional volumes; 4) skeletal and neurobehavioral phenotypes. This work is significant because it determines quantitatively the influence of gonadal sex and sex chromosomes in well-defined sex-specific skeletal traits at the developmental timepoint of their divergence including cellular contributions to these deficits. Additionally, sex-specific effects on behavioral and cognitive phenotypes that are well documented in individuals with DS will be quantified and the contributions of gonadal sex and sex chromosomes will be determined. The work proposed is innovative because it extends well beyond identifying sex as a biological variable; it transcends that to provide a means to determine how sex differences in phenotypes develop. This novel model will be the new standard to determine how sex-specific traits in DS develop in males and females.


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 = $692,850 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Trans-NIH Research Support	000	1	6/23/2026	NEW	$692,850
														Subtotal = $692,850

Grand Total All Awards = $692,850

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New Down syndrome mouse models to understand development of sex-specific co-occurring phenotypes

Award Number: R24OD039898

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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