Genetic Regulatory Network in Craniofacial Development

颅面发育中的遗传调控网络

基本信息

批准号：
10337244
负责人：
Wei Hsu
金额：
$ 66.21万
依托单位：
ADA FORSYTH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337244
关键词：
Abnormal Cell Adult Affect Animal Model Apoptosis Bone Development Bone Diseases Bone Regeneration Calvaria Cartilage Cells Characteristics Childhood Chondrocranium Congenital abnormal Synostosis Craniofacial Abnormalities Craniosynostosis Data Defect Deformity Development Disease Dysplasia Engraftment Etiology Evaluation Exhibits FGFR1 gene Fibroblast Growth Factor Fibrous capsule of kidney Genes Genetic Genomics Growth Health Homeostasis Human Human Development Human Genetics Implant Individual Infant Injury Investigation Joint structure of suture of skull Knockout Mice Laboratories Lentivirus Link Maintenance Mediating Mesenchyme Molecular Morphogenesis Mouse Strains Mus Mutation Natural regeneration Osteoblasts Osteocytes Osteogenesis Pathogenesis Pathway interactions Patients Pfeiffer Syndrome Physiologic Ossification Play Proteins Regulation Repression Role Signal Pathway Signal Transduction Site Skeleton Supporting Cell Surgical sutures Testing Therapeutic Tissues Transplantation Tyrosine bone bone healing bone repair cell type craniofacial craniofacial bone craniofacial development cranium genetic analysis genetic element human disease implantation in vivo inducible gene expression injured insight intramembranous bone formation malformation mouse genetics mouse model novel osteoblast differentiation osteoblast proliferation osteogenic premature receptor repaired reparative capacity self-renewal skeletal skeletal regeneration skeletal stem cell skeletogenesis stem cell division stem cell niche stem cell population stem cells stemness ubiquitin-protein ligase

项目摘要

Title Genetic Regulatory Network in Craniofacial Development Abstract This proposal continues our efforts to decipher the skeletogenic signaling network underlying craniofacial development and disease. The craniofacial skeleton consists of viscerocranium and neurocranium, which is subdivided into the calvarium and chondrocranium. During development of the calvarium, cranial sutures serve as the growth center for skeletogenesis. Defects in suture morphogenesis resulting in premature closure cause craniosynostosis, a devastating childhood disease affecting 1 in ~2,500 individuals. Although human genetic analyses have identified genes associated with the pathogenesis, little is known about the regulation of suture closure essential for development of a healthy skull. In the previously proposed investigation, we have elucidated the mechanisms by which Axin2 regulates suture morphogenesis through modulations of Wnt and downstream signaling pathways. The crosstalk of BMP and FGF signaling plays a pivotal role in Wnt-mediated craniofacial bone development. Furthermore, skeletal stem cells residing in the suture mesenchyme have been successfully identified and isolated in our laboratory. This suture stem cell (SuSC) population is responsible for calvarial development in infants as well as homeostatic maintenance in adults. Upon injury, the dormant SuSCs respond quickly and contribute directly to bone repair in a cell autonomous fashion. In vivo clonal analysis demonstrates calvarial bone regeneration at a single cell level. Implantation of SuSCs to an injured site shows not only long-term survival but also facilitation of bone healing via direct engraftments in which the implanted stem cells give rise to osteogenic cell types in replacement of the damaged tissue. The newly discovered SuSCs thus provides an outstanding opportunity to gain novel insights into etiology of craniosynostosis. In this proposal, we continue our in-depth evaluations of SuSCs by examining their regulation essential for healthy development and homeostasis of the calvarium. We will concentrate on elucidation of molecular and cellular mechanisms underlying craniosynostosis caused by dysregulation of SuSCs.

标题颅面发展中的遗传调节网络抽象的该提案继续我们努力破译颅面颅底的骨骼发明信号网络发展与疾病。颅面骨骼由内脏乳腺癌和神经颅组成，细分为钙和软骨骨。在开发钙钙的开发过程中，颅缝合线服务作为骨骼发生的生长中心。缝合形态发生的缺陷导致过早闭合原因颅骨症，一种毁灭性的儿童疾病，影响了约2500名患者。虽然人类遗传分析已经确定了与发病机理相关的基因，对缝合的调节知之甚少闭合对于发展健康的头骨至关重要。在先前提出的调查中，我们有阐明了Axin2通过Wnt和下游信号通路。 BMP和FGF信号传导的串扰在WNT介导的颅面发育。此外，居住在缝合缝隙间充质中的骨骼干细胞已经在我们的实验室中成功识别和孤立。该缝合干细胞（SUSC）人群负责婴儿的颅骨发育以及成人的稳态维护。受伤后，休眠 SUSC迅速做出反应，并直接以细胞自主的方式为骨骼修复做出了贡献。体内克隆分析表明颅骨再生在单细胞水平上。将SUSC植入受伤站点不仅显示长期生存，而且还通过直接植入来促进骨骼愈合植入的干细胞在替换受损组织时会引起成骨细胞类型。新的因此，发现的SUSC提供了一个很棒的机会，以获取对病因的新颖见解颅突式症。在此提案中，我们通过检查他们的SUSC进行了深入的评估对钙瓦尔宫健康发展和稳态至关重要的调节。我们将集中精力阐明颅颅突出的分子和细胞机制，导致因失调的失调而导致 SUSC。