CRANIOSYNOSTOSIS AND SUTURE BIOLOGY

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Craniosynostosis is the morbid condition of premature fusion of calvarial bones. The sequelae of premature calvarial sutural fusion include 1) increased intracranial pressure associated with brain injury, 2) skull malformations requiring extensive surgical correction, and 3) abnormal development of the zygoma and maxilla necessitating orthodontic management and orthognatic surgery. Despite the rapid advance of our understanding of the molecular etiology of hereditary synostosis, the biological basis of craniosynostosis has yet to be elucidated. Over the past four years we have learned that mutations of fibroblast growth factor receptor family (FGFRs) and the TWIST are responsible for the majority of cases of syndromic synostosis. In order to understand the biology behind hereditary suture fusion, we propose to: 1) determine whether osteoblasts derived from patients with syndromic synostosis, harboring FGFR2, FGFR3, or TWIST mutations, will induce premature closure of rat coronal sutures 2) establish whether changes in suture development induced by mutant osteoblasts are due to intrinsic differences in mutant osteoblast growth and bone formation (e.g. cell autonomous) or the elaboration of cytokines which effect suture development and 3) correlate changes induced in suture development by mutant osteoblasts with changes in apoptotic cell death, mitogenic activity, and/or rates of matrix formation or mineralization. In order to test the hypothesis that: Syndromic craniosynostosis in humans is mediated by osteoblasts and their influence on the microenvironment of the calvarial suture. We propose that changes in osteoblast growth, mitotic rate, resistance to apoptosis and/or elaboration of cytokines results in premature suture fusion and craniosynostosis. These studies will lead to important information about the biology behind the development of craniosynostosis and may have significant implications for the treatment and primary prevention of synostosis in humans.