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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