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 for careers in the biomedical sciences to continue investigations of Ts21 and other disorders.
The proposed research is relevant to public health because it will identify genetic, cellular and molecular bases of skeletal phenotypes related to Down syndrome, as well as differences between the sexes in bone development related to Trisomy 21. The projects outlined in this proposal will be done with a team primarily composed of undergraduate students and will strengthen the research environment at IUPUI. The proposed research is relevant to the part of NICHD?s mission to insure that that all children have the chance to achieve their full potential free from disease or disability.
