Genetic and developmental pathways causing midface hypoplasia

描述（由申请人提供）：颅缝早闭是临床上最显着的颅面异常之一，其特征是一个或多个颅缝（分离颅骨的非矿化间充质区域）的病理性过早融合。面中部发育不全是颅缝早闭的一个突出但研究不足的并发症，也是一个常见的临床问题。虽然我们对综合征性颅缝早闭的分子发病机制的理解取得了进展，但对这些突变的生物学效应或相关的面中部发育不全的发病机制知之甚少。我们的项目将利用最先进的基因组测序技术，以确定遗传原因和干扰下游分子途径的患者和新的小鼠突变体，共同存在面中部发育不全和颅缝早闭。此外，我们建议利用一个独特的和强大的转基因小鼠系的组合，以帮助在不同的小鼠模型中的面中部发育不全的细胞和发育基础的表征。这些研究将为正常面部缝合生物学、面中部生长和畸形学的重要遗传途径和细胞机制提供重要的新见解。最后，希望更好地了解面中部发育不全的发病机制将导致改善患者的临床和手术管理的有效性和时机。

DESCRIPTION (provided by applicant): Craniosynostosis is among the most clinically significant craniofacial anomalies and is characterized by the pathologic premature fusion of one or more cranial sutures, the regions of non-mineralized mesenchyme separating the cranial bones. Midfacial hypoplasia is a prominent but understudied co-morbidity of craniosynostosis as well as a common clinical problem as an isolated anomaly. Although advances have been made in our understanding of the molecular pathogenesis of syndromic craniosynostosis, little is understood about the biologic effects of these mutations or the pathogenesis of associated midfacial hypoplasia. Our project will utilize state of the art genome sequencing technologies to identify genetic causes and the perturbed downstream molecular pathways in patients and new mouse mutants that co-present with midfacial hypoplasia and craniosynostosis. In addition, we propose to utilize a combination of unique and powerful transgenic mouse lines to aid in characterization of the cellular and developmental basis of midface hypoplasia in the various mouse models. These studies will provide significant new insight into the genetic pathways and cellular mechanisms important for normal facial suture biology, midfacial outgrowth, and dysmorphology. Ultimately, it is hoped that a greater understanding of the pathogenesis of midfacial hypoplasia will lead to improvements in effectiveness and timing of the clinical and surgical management of patients.