Activating mutations in the FGFR3 tyrosine kinase account for several forms of human dwarfism, including achondroplasia, the most common form of human short-limb dwarfism, and a neonatal-lethal thanatophoric dysplasia. Although achondroplasia is considered potentially treatable, there is no cure available at present. This is mostly due to our poor understanding of the mechanism of FGFR3 action in cartilage. Specific inhibition of known FGFR3 signaling pathways in cartilage rescues the FGFR3 effects only partially, strongly suggesting the existence of yet unknown pathways. Our proposal aims on discovery of such pathways through screening of molecular library. Using both chemical and genetic approaches, we will identify and characterize novel pathways of aberrant FGFR3 signaling in cartilage. This should lead to a better understanding of FGFR3 signaling in cartilage so that a treatment for achondroplasia can be found. (en)
Cílem projektu je objevit nové signální dráhy FGFR3 receptorové tyrozin-kinázy v chrupavce metodou skríningu molekulární knihovny. Účelem projektu je (A) objasnění mechanizmu patologického FGFR3 signalingu v achondroplázii a (B) identifikace potenciálních možností léčby tohoto onemocnění.