# Development and treatment of skeletal deficits in a Down syndrome mouse model

> **NIH NIH R15** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $451,736

## Abstract

ABSTRACT
 Skeletal abnormalities occur in all individuals with Trisomy 21 (Ts21). In contrast to most other bone
abnormalities leading to osteoporosis, the bone deficits found in individuals with Down syndrome (DS) arise
during developmental instead of older ages. Significant differences in bone deficits between males and
females with DS have begun to be recognized in adults. In adolescents with Ts21, however, differences in the
development and manifestation of skeletal abnormalities between sexes are not well defined, largely because
of small sample sizes and analyses of adolescent males and females with DS together. The cellular and
molecular aspects leading to DS-related bone abnormalities are also not clear, as they have previously been
examined using small samples often limited to one sex and/or a few distinct ages. Work from the PI’s
laboratory has shown that skeletal deficits occur in DS mouse models that are analogous to those found in
humans, and that the trisomic gene Dyrk1a plays a significant role in DS-associated skeletal deficits. During
the last funding period, work from undergraduate and graduate students demonstrated a distinct sexual
dimorphism in the occurrence and severity of appendicular skeletal deficits in DS mouse models. Additionally,
the results showed that EGCG, the most common green tea polyphenol and an in vitro inhibitor of DYRK1A
activity, when given in higher dosages and for longer periods of time, does not correct DS skeletal deficits,
does not inhibit DYRK1A activity in vivo, and may be detrimental to bone phenotypes. The proposed research
seeks to overcome three barriers to treatment of skeletal (and all) deficits associated with DS. First, this
research will establish differences in skeletal deficits between adolescent trisomic male and female mice.
Second, this project will determine the cellular mechanisms that are disturbed in bone by trisomy, and if
disruptions in osteoblasts and osteoclasts are different throughout trisomic development and sex-specific.
Third, this work will ascertain sex-specific molecular mechanisms via which trisomic Dyrk1a causes bone
abnormalities. Using innovative DS mouse models, the proposed work to be done primarily by undergraduate
students concentrates on identifying sexual dimorphisms and differential temporal effects in skeletal deficits
related to DS. Additionally, the proposed work will test the hypothesis that overexpression of Dyrk1a, at
different critical points in development, leads to differing bone deficits in trisomic males and females. This
project will provide undergraduate students with significant biomedical research experiences to answer
fundamental questions about skeletal development in DS and provide a foundation for potential therapies to
correct bone abnormalities in DS. Involvement of students in this work will enhance the research environment
at Indiana University-Purdue University Indianapolis and provide an excellent foundation to undergraduate
students ...

## Key facts

- **NIH application ID:** 10114596
- **Project number:** 2R15HD090603-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** RANDALL J ROPER
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,736
- **Award type:** 2
- **Project period:** 2017-07-07 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114596

## Citation

> US National Institutes of Health, RePORTER application 10114596, Development and treatment of skeletal deficits in a Down syndrome mouse model (2R15HD090603-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114596. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*