Genetic and developmental pathways causing midface hypoplasia

描述(申请人提供)：颅缝融合是临床上最显著的颅面畸形之一，其特征是一条或多条颅缝的病理性过早融合，即分隔颅骨的非矿化间充质区域。面中部发育不全是颅缝发育不全的一种常见的临床问题，也是一种常见的孤立性畸形，是一种突出但尚未被研究的共同疾病。虽然我们对综合征性颅缝早闭的分子发病机制的了解已经取得了进展，但对这些突变的生物学效应或相关的面中部发育不良的发病机制还知之甚少。我们的项目将利用最先进的基因组测序技术来确定遗传原因和患者以及与面中部发育不良和颅缝融合共存的新的小鼠突变的下游分子通路。此外，我们建议利用独特和强大的转基因小鼠系的组合来帮助描述各种小鼠模型中面中部发育不良的细胞和发育基础。这些研究将为正常面部缝合生物学、面中部生长和畸形的遗传途径和细胞机制提供重要的新见解。最终，希望更多地了解面中部发育不良的发病机制将导致改善患者的临床和手术治疗的有效性和时机。

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.