Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

 描述（由申请人提供）：颅缝早闭是一种使人衰弱的疾病，其特征是颅缝过早融合，导致颅骨形状异常。耳聋、失明和智力迟钝常常伴随着这一发现，通常需要进行广泛的手术。颅缝早闭的估计患病率为1：2，500活产，使其成为影响骨骼系统的最常见的先天性畸形之一。提出的研究的长期目标是确定BMP信号传导组分中的功能获得性突变导致颅缝早闭的分子机制。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然未知。最近提出了BMP信号在颅缝早闭中的作用。我们开发了一种新的小鼠颅缝早闭模型，其特征是通过BMP信号传导成分中的功能获得性突变使额缝过早融合。该模型是独特且重要的，这是由于：1）观察到p53诱导的细胞凋亡的上调，2）在过早融合之前在融合位点形成异位软骨，以及3）在Bmprla的杂合无效背景中拯救了表型，表明BMP信号传导的精确控制对于预防颅缝早闭至关重要。总之，这些发现提示了缝线过早融合的新机制。我们将确定颅缝早闭的关键下游分子和信号通路，并建立使用特定信号通路的化学抑制剂结合我们新开发的基因沉默方法的治疗方法。我们的研究将进一步确定直接参与导致颅缝早闭的颅缝过早融合发病机制的分子途径，并将为人类病例治疗过程中的潜在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.