NIH grant: New Down syndrome mouse models to understand development of sex-specific co-occurring phenotypes (1R24OD039898-01)

retained text

NIH grant 1R24OD039898-01: New Down syndrome mouse models to understand development of sex-specific co-occurring phenotypes
Institute: {'code': 'OD', 'abbreviation': 'OD', 'name': 'NIH Office of the Director', 'admin_org_id': '12500055', 'admin_funding_url': ''}. PI: RANDALL J ROPER. Award: $692850.
Start: 2026-07-01T00:00:00.
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.

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