CRANIOSYNOSTOSIS AND SUTURE BIOLOGY

颅骨融合是颅骨过早融合的病态状态。颅骨缝合过早融合的后遗症包括：1)合并脑损伤的颅内压升高，2)颅骨畸形需要广泛的手术矫正，3)颧骨和上颌骨发育异常，需要正畸治疗和正畸手术。尽管我们对遗传性融合的分子病因学的认识有了长足的进步，但颅性融合的生物学基础仍未阐明。在过去的四年里，我们了解到成纤维细胞生长因子受体家族(FGFRs)的突变和TWIST是导致大多数综合征性联会的原因。为了了解遗传性骨缝融合背后的生物学基础，我们建议：1)确定来自综合征性骨缝融合患者的成骨细胞是否会导致大鼠冠状缝过早关闭；2)确定突变成骨细胞诱导的缝合发育变化是否是由于突变成骨细胞生长和骨形成(如细胞自主)的内在差异或影响缝合发育的细胞因子的产生；3)突变成骨细胞诱导的缝合发育变化与细胞凋亡、有丝分裂活性和/或基质形成或矿化速率的变化是否相关。为了验证这一假设：人类的综合征性颅缝闭合是由成骨细胞及其对颅缝微环境的影响所介导的。我们认为，成骨细胞生长、有丝分裂速率、抗凋亡和/或细胞因子分泌的改变导致过早缝合融合和颅缝融合。这些研究将提供有关颅缝融合形成的生物学基础的重要信息，并可能对人类颅缝融合的治疗和初级预防具有重要意义。

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.