Integrated development and modulation of the brain, bones and cognition in the context of Down syndrome

Trisomy of chromosome 21 in Down syndrome (DS) leads to intellectual disability, craniofacial and skeletal dysmorphologies. As in many neurodevelopmental disorders, the DS phenotype relies on altered development and crosstalk between tightly integrated tissues. Neural and skeletal morphogenesis are linked through common signalling pathways, with a prominent role for Dyrk1A, a key gene in neural, but also craniofacial development and bone homeostasis. We hypothesize that cognition, brain and bones may be coordinately affected by DYRK1A overdosage in DS and therefore corrected through Dyrk1A inhibition. We will combine psychomotor and cognitive tests with longitudinal in-vivo imaging to follow the neural and skeletal development of Ts65Dn, a DS mouse model, from birth to adulthood. We aim to evaluate the integration of neural and skeletal development in normal and trisomic mice, upon modulation of DYRK1A-activity by epigallocatechin-galate, a green tea flavonoid. Thereby we will identify the prenatal dose that optimizes the integrated development of brain, skull and bones and correlates to cognitive improvement in DS. This addresses the unknowns underlying the search for persistent therapeutic effects while minimizing potential side effects, such as brain and skeletal malformations associated with disabilities that compromise the quality of life with DS. The resulting knowledge will be key to our understanding of pathogenesis and to the design of clinical studies addressing prenatal treatment of DS.

Jaar van publicatie:2023

Toegankelijkheid:Open