Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

 描述(申请人提供)：颅缝融合是一种衰弱的情况，其特征是颅缝过早融合，导致头骨形状异常。耳聋、失明和智力低下常常伴随着这种发现，通常需要进行一系列广泛的手术。据估计，颅骨融合症的患病率为1：2,500活产儿，使其成为影响骨骼系统的最常见的先天性畸形之一。所提出的研究的长期目标是确定BMP信号成分的功能获得突变导致颅性融合的分子机制。最近的研究表明，颅缝早闭与几个基因的突变有关；然而，大多数(70%)颅缝早闭的遗传原因仍不清楚。骨形态发生蛋白信号转导通路参与了颅缝融合的研究。我们开发了一种新的小鼠颅缝融合模型，其特征是通过BMP信号组件的功能获得突变来过早融合异位缝合。这个模型是独特而重要的，因为：1)观察到P53诱导的细胞凋亡上调，2)在早熟融合之前融合部位形成了异位软骨，3)在BMPR1A杂合缺失的背景下挽救了表型，这表明精确控制BMP信号是预防颅缝融合的关键。综上所述，这些发现提示了过早缝合融合的新机制。我们将确定颅缝融合症的关键下游分子和信号通路，并建立针对特定信号通路的化学抑制剂与我们新开发的基因沉默方法相结合的治疗方法。我们的研究将进一步明确直接参与颅缝过早融合导致颅突融合的发病机制的分子途径，并将为人类病例治疗过程中潜在的分子靶点提供更好的见解。

 DESCRIPTION (provided by applicant): Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion resulting in abnormal skull shape. Deafness, blindness, and mental retardation often accompany this finding and an extensive series of surgeries is commonly required. The estimated prevalence of craniosynostosis is 1:2,500 live births making it one of the most prevalent congenital malformations affecting the skeletal system. The long- term goal of the proposed studies is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Recent studies show craniosynostosis is associated with mutations in several genes; however, genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling in craniosynostosis has been recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of the metopic suture via gain-of-function mutation in a BMP signaling component. This model is unique and important due to: 1) upregulation of p53- induced apoptosis is observed, 2) ectopic cartilage is formed at the site of fusion prior to premature fusion, and 3) the phenotype is rescued in the heterozygous null background of Bmpr1a indicating precise control of BMP signaling is critical for preventing craniosynostosis. Together these finding suggest novel mechanisms for premature suture fusion. We will identify critical downstream molecules and signaling pathways for craniosynostosis and establish treatment methods using chemical inhibitors for specific signaling pathways coupled with our newly developed gene silencing method. Our study will further define molecular pathways directly involved in the pathogenesis of premature fusion of cranial sutures leading to craniosynostosis and will provide better insights for potential molecular targets during therapeutic treatment of human cases.