DESCRIPTION (provided by applicant): Congenital birth defects are the leading cause of infant deaths in the United States. About 1 in 2500 children is born with craniosynostosis, a congenital birth defect that is characterized by premature fusion of the flat bones of the skull resulting in abnormal growth of the skull. Significant health problems are associated with craniosynostosis syndromes and surgical intervention is the only recourse for children with this problem. In order to develop alternative strategies for treatment of these defects, a clear understanding of bone development is essential. Bones form by intramembranous (direct formation of bone) or by endochondral (initial formation of cartilage and later replacement by bone) ossification. How cell-intrinsic factors, such as transcription factors, regulate these two differentiation programs have been studied in detail. However, extrinsic signals that initiate these alternate modes of development have not been clearly defined. Our long-term goal is to understand how extracellular signals, such as FGFs (fibroblast growth factor), regulate early cell fate decisions that determine the choice between endochondral and intramembranous ossification in vivo. To this end, we will use a transgenic line (OVE1070) we have generated that shows an altered pattern of differentiation of the parietal bones of the skull. In these mice, the cranial mesenchymal cells that form the parietal bones switch from intramembranous to endochondral ossification. Our preliminary results support the hypothesis that this switch in the parietal bone differentiation program is due to Fgf9 transgene expression in the cranial mesenchymal precursors. The Specific Aim will test this hypothesis by replication of the OVE1070 phenotype by generation of transgenic mice with targeted expression of Fgf9 in the cranial mesenchymal precursors. As an outcome of the proposed investigations, we expect to elucidate an early (and a novel) role for FGF signaling in regulation of early cell fate decisions involved in skeletal growth and differentiation. As mutations in FGF receptors and impaired FGF signaling have been shown to be associated with craniosynostosis in humans, a clear understanding of the ways in which FGF signaling modulates skeletal differentiation is critical for understanding the causes for craniosynostosis and defining possible targets for therapy.
|Effective start/end date||7/1/06 → 6/30/08|
- National Institutes of Health: $71,750.00
- National Institutes of Health: $69,669.00