This application seeks to understand the biology regulating physiologic and pathologic cranial suture fusion to facilitate the development of therapies to treat human craniosynostosis. With an incidence of 1:2000 world-wide, craniosynostosis represents a significant biomedical burden. Children with craniosynostosis require complex reconstructive surgery associated with significant morbidity. We will study the molecular and cell biology regulating fusion of cranial sutures in mice. In the first part of our application will use microarray analysis to identify differences in the genomic blueprints of regionally differentiated dura from patent and fusing sutures of mice. The data derived from these studies will be used to identify genes that are candidates for regulators of cranial suture and osteoblast biology, and will be further tested in our coculture model to establish their functional role in suture biology. The second part of our application will study the effects of regional dura mater, the primary regulator of suture fusion or patency, on osteoblast biology using a novel dura mater-osteoblast co-culture system. This system will enable us to manipulate the signaling between dura mater and calvarial osteoblasts to determine the paracrine mechanisms mediating suture fate. The third part of this application will determine how FGF signaling regulates suture fusion. We will manipulate the biology of FGF-2 ligand and FGF-R2 null mutants both in cell culture and in vivo in order to determine the mechanism(s) of FGF mediated suture fusion. In the fourth part of this application we will investigate the function of Noggin, a BMP antagonist capable of maintaining suture patency. We will use Noggin null mutants, and Noggin antisense adenovirus, to determine whether Noggin is required to maintain embryonic and post-natal suture patency, respectively. We will then use a double transgenic mouse (FGFR1 / Noggin-LacZ ) to examine the effects of increased FGF signaling on Noggin expression in a pathologically fusing suture. Finally, pathologically fusing sutures will be rescued with perinatal gene therapy using a Noggin adenovirus.
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