CRANIOSYNOSTOSIS AND SUTURE BIOLOGY

颅缝早闭是颅骨过早融合的病态。颅骨缝过早融合的后遗症包括1）与脑损伤相关的颅内压升高，2）需要广泛手术矫正的颅骨畸形，以及3）需要正畸治疗和正颌外科手术的颌骨和上颌骨发育异常。尽管我们对遗传性骨缝早闭的分子病因学的理解取得了迅速的进展，但颅缝早闭的生物学基础还有待阐明。在过去的四年中，我们已经了解到，成纤维细胞生长因子受体家族（FGFR）和TWIST的突变是大多数综合征性骨结合病例的原因。为了了解遗传性缝融合背后的生物学，我们建议：1）确定成骨细胞是否来源于具有综合征性骨结合症的患者，携带FGFR 2、FGFR 3或TWIST突变，将诱导大鼠冠状缝的过早闭合2）确定由突变成骨细胞诱导的缝发育的变化是否是由于突变成骨细胞生长和骨形成的内在差异（例如，细胞自主的）或影响缝线发育的细胞因子的加工，以及3）将突变成骨细胞在缝线发育中诱导的变化与凋亡性细胞死亡、促有丝分裂活性和/或基质形成或矿化速率的变化相关联。为了验证这一假设：人类综合征性颅缝早闭是由成骨细胞介导的，它们对颅缝微环境的影响。我们认为成骨细胞生长、有丝分裂率、细胞凋亡抵抗和/或细胞因子的产生导致骨缝过早融合和颅缝早闭。这些研究将导致有关颅缝早闭发展背后的生物学的重要信息，并可能对人类骨缝早闭的治疗和一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.