Genetic and developmental pathways causing midface hypoplasia

描述（由申请人提供）：颅缝闭闭是临床上最重要的颅面异常之一，其特征是一条或多条颅缝的病理性过早融合，颅缝是分隔颅骨的非矿化间质区域。面中部发育不全是颅缝闭锁的一个突出但研究不足的合并症，也是一个常见的临床问题，作为一个孤立的异常。虽然我们对综合征性颅缝闭闭的分子发病机制的理解已经取得了进展，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来确定患者和新小鼠突变体的遗传原因和受干扰的下游分子途径，这些突变体共同存在于面中发育不全和颅缝闭锁中。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表征各种小鼠模型中面部发育不全的细胞和发育基础。这些研究将为正常面部缝合生物学、面部中部生长和畸形学的遗传途径和细胞机制提供重要的新见解。最终，我们希望对面中发育不全的发病机制有更深入的了解，从而提高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. PUBLIC HEALTH RELEVANCE: The causes and mechanisms underlying the clinical presentation of craniosynostosis-associated midfacial hypoplasia remains poorly understood, despite the significance of the clinical problem. The vast majority of biologic research has focused on the pathogenesis of calvarial bone fusion while ignoring the co-morbid association of midfacial hypoplasia, which often leads to life threatening airway compromise and the need for extensive reconstructive orthognathic surgery. Closing these gaps in our knowledge of the pathogenesis of craniofacial synostosis is vital to the development of appropriate, evidence-based care for this patient population.