Craniosynostosis premature fusion of the skull bones at the sutures, is a relatively common birth defect that affects 1 in 3000 live births. Craniosynostosis represents a significant biomedical burden because the only way to correct this abnormal suture morphogenesis is to surgically separate the prematurely fused calvarial bones. Insight into the mechanism of craniosynostosis was gained recently by the discoveries that mutations in the homeobox gene MSX2, and the growth factor receptors FGFR1, FGFR2 and FGFR3, lead to premature suture fusion. Although intrauterine compression and abnormal forces transmitted by the cranial base have also been implicated in premature suture fusion, the molecular mechanisms that regulate these events are unknown.
The specific aims outlined in this proposal will test the hypothesis that mechanical forces applied to the developing calvarium lead to changes in molecular mediators (genes, growth factors and signalling molecules) that regulate normal and abnormal suture morphogenesis in vitro. Molecular mediators that have been shown to be involved in craniosynostosis will be studied, and a differential screening strategy will be undertaken to identify novel genes that regulate force- induced suture morphogenesis. We have created a mouse model of craniosynostosis, Boston type by misregulation of the homeobox gene MSx2; this mouse model will be used to determine if the alterations in the molecular mediators induced by force are also present in craniosynostosis Boston type. Similar alterations in molecular mediators would suggest common signaling pathways between mechanically-induced and genetically- based craniosynostosis. The long term goals of this study are to gain insight into the molecular mechanisms by which biomechanical force regulates the development of maintenance of skeletal articulations and to utilize these mechanisms in therapeutic interventions to reduce morbidity associated with craniosynostosis and other skeletal diseases.

Project Start
2001-01-01
Project End
2002-12-31
Budget Start
Budget End
Support Year
23
Fiscal Year
2001
Total Cost
$115,227
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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