Specific skeletal deficits are manifest in all individuals with Down syndrome (DS) but have not been extensively studied. As individuals with DS are living longer, they are increasingly at risk for fractures and osteoporosis that result from skeletal deficiencies. Limited studies of humans with DS show a sexual dimorphism in the development of skeletal deficits, but these differences have also not been well defined. DS mouse models have shown that both bone formation and resorption parameters are affected by trisomy. Genetic studies have shown that overexpression of Dyrk1a, a gene found in three copies in humans with DS as well as in DS mouse models, significantly contributes to DS skeletal deficits. Therapeutic modulations of the DS skeletal phenotypes in mice show that Epigallocatechin gallate (EGCG), an inhibitor of Dyrk1a activity, may improve certain skeletal phenotypes associated with DS. The long-term goal of our research is to understand the molecular, cellular and genetic bases of skeletal phenotypes in DS and develop effective screening, therapeutic and preventive strategies. The objectives of this application are to use DS mouse models to: 1) delineate how development of skeletal deficits differs in males and females with DS, 2) quantify how changing dose and duration of EGCG treatment influences skeletal phenotypes and 3) identify the relative contributions of bone forming and resorbing cells in DS skeletal phenotypes. Our central hypothesis is that an optimal treatment and dosage of EGCG will correct cellular bone deficits and improve skeletal strength in both males and females when administered at an optimal time in development. The rationale for this proposal is to provide necessary preclinical information that will lead to the correction of bone deficits in individuals with DS. This endeavor is significant and timely because it defines sex specific differences in, cellular origins of and etiologically-based treatments for skeletal phenotypes found in all males and females with DS. This proposal is innovative because it will extensively characterize the cellular basis of the skeletal deficits in DS. Additionally, it will quantify for the first time the sexual dimorphism, vertebrate deficiencies, and contribution of trisomic Dyrk1a in bone forming and resorbing activities in skeletal phenotypes of two different DS mouse models. Completion of these aims is expected to provide mechanisms for the sexual dimorphisms in the development of skeletal deficits in DS and propose rational treatments to correct these deficits. This etiological-based treatment of skeletal deficits in a DS mouse model will have a positive impact by providing a preclinical foundation for testing similar pharmacotherapies in individuals with DS.

Public Health Relevance

The proposed research is relevant to public health because it identifies sexual dimorphism, development and treatment of skeletal phenotypes related to Down syndrome. 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 and relevant to the part of NIAMS's mission to support research into the causes, treatment, and prevention of musculoskeletal diseases as well as train basic scientists to carry out this research.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1)
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Winer, Karen
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Indiana University-Purdue University at Indianapolis
Schools of Arts and Sciences
United States
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