PROJECT SUMMARY/ABSTRACT Treatment of cognitive deficits associated with Down syndrome (DS) has become a realistic goal, yet most potential therapies have not overcome translational barriers from preclinical animal models to clinical trials in humans with Trisomy 21 (Ts21). Numerous preclinical treatments in mouse models—usually targeting neurobehavioral disorders—have attempted to treat DS phenotypes with approaches that: a) assume expression of a single gene at trisomic levels throughout the lifespan causes the trait; b) consider trisomy as causing changes to developmental mechanisms that lead to a particular phenotype; or c) treat existing DS phenotypes symptomatically. These methods, commonly studied in just one sex in mouse models, have often reported at least transient improvement in neurobehavioral phenotypes. Translation of these one-dimensional preclinical therapies to humans with Ts21 has been largely unsuccessful, potentially because treatments implemented did not explicitly target mechanisms active during the origins of the abnormal developmental trisomic trajectories nor consider sex-specific processes in the DS mouse models. One conventional view is that trisomic gene expression is generally upregulated 1.5-fold that of normal regardless of developmental stage, and that reducing this gene expression or activity to normal levels at any period can improve a trait. Our long-term goal challenges this view with an innovative alternative strategy for identifying windows of opportunity for effective therapeutics by targeting trisomic gene mediated developmental origins of aberrant cognitive and skeletal phenotypes in individuals with Ts21. This fundamentally new approach to treatment of DS phenotypes is driven by novel data that DYRK1A protein overexpression in trisomic mice is temporally regulated and is amplified in the brain specifically during early postnatal development. This paradigm shift to a combined developmental-genotype-phenotype approach that also addresses sex differences transcends current treatment approaches. The aims of this proposal use a novel trisomic model that manipulates the timing of inducible functional reduction of Dyrk1a during specific windows of development. It tests the hypotheses that amplified (dysregulated) expression of Dyrk1a during temporally-defined windows of development—evident both in brain and in bone—mark the origins of sex-dependent aberrant trajectories of DS phenotypes, and provide windows of opportunity for genetic normalization to improve DS phenotypes. Completion of this transformational project is expected to provide the strongest available evidence for pursuing sex-specific pharmacogenetic treatments that target DYRK1A during critical temporal windows of early development in humans with DS to improve neurocognitive and comorbid skeletal outcomes. If successful, the strategic approach will transform how treatments are devised, tested, and effectively translated into humans with DS, by firs...