Genetic and developmental pathways causing midface hypoplasia

导致中面部发育不全的遗传和发育途径

基本信息

批准号：
8461552
负责人：
Timothy Chilton Cox
金额：
$ 79.04万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-20 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461552
关键词：
Algorithms Animal Model Apert syndrome Appearance Biological Biological Assay Biology Calvaria Candidate Disease Gene Caring Cell Culture Techniques Cell Death Cell Proliferation Cells Cephalic Chromosomes Clinical Clinical Management Comorbidity Complement Complex Congenital abnormal Synostosis Craniosynostosis Data Development Dysmorphology Ectopic Expression Effectiveness Etiology Exhibits Face Genes Genetic Genome Goals Growth Histology Human In Situ Hybridization Investigation Joint structure of suture of skull Knock-in Mouse Knowledge Lead Life Maps Maxilla Mediating Mesenchyme Modeling Molecular Molecular Profiling Mus Mutant Strains Mice Mutation Neural Crest Operative Surgical Procedures Osteoblasts Paraxial Mesoderm Parents Pathogenesis Pathologic Pathway Analysis Pathway interactions Patients Phenotype Population Population Control Process RNA RNA Interference Recurrence Reporter Research Role Specificity Staging Surgical Management Surgical sutures Syndrome System Technology The Jackson Laboratory Time Tissue-Specific Gene Expression Transgenic Mice Transgenic Organisms Variant X-Ray Computed Tomography base bone cell type clinically significant coronal suture craniofacial developmental genetics evidence base exome sequencing genome sequencing genome-wide insight interest lentiviral-mediated malformation midfacial hypoplasia mouse model mutant novel orthognathic osteogenic patient population premature response skull base suture fusion theories transcriptome sequencing

项目摘要

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.

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，其特征是一根或多根颅缝（分隔颅骨的非矿化间质区域）的病理性过早融合。面中部发育不全是颅缝早闭的一种突出但尚未得到充分研究的并发症，也是一种常见的临床问题，是一种孤立的异常现象。尽管我们对综合征性颅缝早闭的分子发病机制的理解已取得进展，但对这些突变的生物学效应或相关面中部发育不全的发病机制了解甚少。我们的项目将利用最先进的基因组测序技术来识别患者和与中面发育不全和颅缝早闭共存的新小鼠突变体的遗传原因和受干扰的下游分子途径。此外，我们建议利用独特且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中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、中面部生长和畸形重要的遗传途径和细胞机制提供重要的新见解。最终，希望对面中部发育不全的发病机制有更深入的了解，从而提高患者临床和手术治疗的有效性和时机。