Midface and Upper Airway in Craniosynostosis

描述（由申请人提供）：颅缝闭合是一种常见的出生缺陷，可以作为综合征的一部分或作为孤立的异常发生。虽然通常被定义为颅穹窿缝合线过早闭合，但解剖学和临床研究显示整个头部的复杂畸形。颅缝闭锁综合征的一个典型的复杂特征是“面中发育不全”，这是一种笼统的诊断，根据上颚、鼻咽和颧骨发育不足来定义，表现为面部比平均水平平坦，并伴有呼吸困难。我们有来自人类和小鼠颅缝闭合模型的新数据，这些数据详细描述了受各种FGFR2和FGFR3突变不同影响的颅穹窿、颅底、面部骨骼、面部缝合线和上呼吸道的精确方面。我们假设，“面中发育不全”的普遍情况代表了一种复杂的表型，其组成部分因特定突变而异。颅缝闭闭的致病突变如何影响发育中的颅面复合体的细胞和组织，从而导致面中部和后肛门发育不全或闭锁，目前所知相对较少。在这个项目中，我们将对来自的3D图像数据进行定量分析

DESCRIPTION (provided by applicant): Craniosynostosis is a common birth defect that can occur as part of a syndrome or as an isolated anomaly. Though often defined as the premature closure of a cranial vault suture, anatomic and clinical studies reveal complex dysmorphology of the entire head. One complex trait typical of craniosynostosis syndromes is 'midfacial hypoplasia', a catch-all diagnosis that is defined on the basis of deficient development of the upper jaw, nasopharynx, and cheekbones presenting with a flatter than average face and associated respiratory difficulties. We have novel data from humans and mouse models of craniosynostosis which detail precise aspects of the cranial vault, cranial base, facial skeleton, facial sutures, and upper airway that are differentially affected by various FGFR2 and FGFR3 mutations. We hypothesize that the generalized condition of 'midfacial hypoplasia' represents a complex phenotype whose component parts differ depending upon the specific mutation. Relatively little is known about how the mutations identified as causative in craniosynostosis affect cells and tissues of the developing craniofacial complex to result in midfacial and choanal hypoplasia or atresia. In this project, we will perform quantitative analysis of 3D image data from human craniosynostosis phenotypes to formulate and test hypotheses pertaining to localized effects of various mutations in mouse models with craniosynostosis. We will use conditional mutant mice including Fgfr2+/S252W and Fgfr2+/P253R Apert syndrome, Fgfr2cC342Y/+ Crouzon/Pfeiffer syndrome, and Fgfr3+/P244R Muenke syndrome, and Wnt1-, Mesp1- and Sox17-2A-I-Cre-reporter mice to quantitatively study the differential effects of these mutations on specific craniofacial structures and cells and tissues that are derived from diverse embryonic tissues and that contribute to 'midfacial hypoplasia'. Once these precise phenotypic effects are defined on facial and cranial base phenotypes, we will analyze the role of these mutations on cell migration, differentiation, apoptosis, and proliferation. Finally, using RNA-seq, in situ hybridization, immunoblots, and immunohistochemistry on tissues micro-dissected from specific regions and developmental stages, we will scrutinize candidate Fgfr pathways (e.g., Erk1/2, p38) and identify novel pathways. We will provide essential information on dysmorphogenesis of the upper airway and face and establish objective criteria for the definition of midfacial and choanal hypoplasia needed to improve healthcare for numerous patients with these conditions. PUBLIC HEALTH RELEVANCE: Midfacial hypoplasia, a general term that describes a disproportionately small face, is a common feature of many craniofacial diseases including craniosynostosis syndromes. Midfacial hypoplasia involves developmental defects of various skeletal components and/or soft tissue organs and spaces such as the upper airway. We will use 3D data from craniosynostosis patients to quantitatively define these abnormalities and to guide investigations in mouse models to determine the underlying molecular, cellular and developmental basis of these disorders. Through these studies we will ultimately gain insights to improve care of patients with these conditions.