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：
10440858
负责人：
Wei Hsu
金额：
$ 50.66万
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/10440858
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 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.

标题颅面发育中的遗传调控网络抽象的该提案继续我们破译颅面部潜在骨骼信号网络的努力发育和疾病。颅面骨骼由脏颅骨和神经颅骨组成，又分为颅骨和颅软骨。在颅骨发育过程中，颅缝起到作为骨骼形成的生长中心。缝线形态发生缺陷导致过早闭合的原因颅缝早闭是一种毁灭性的儿童疾病，影响约 2,500 人中的 1 人。虽然人类遗传分析已确定与发病机制相关的基因，但对缝线的调节知之甚少闭合对于健康颅骨的发育至关重要。在之前提出的调查中，我们已经阐明了 Axin2 通过调节 Wnt 和下游信号通路。 BMP 和 FGF 信号的串扰在 Wnt 介导中起着关键作用颅面骨发育。此外，存在于缝合间充质中的骨骼干细胞已被在我们的实验室成功鉴定和分离。该缝线干细胞 (SuSC) 群负责婴儿的颅骨发育以及成人的体内平衡维持。受伤后，休眠状态 SuSC 反应迅速，并以细胞自主的方式直接促进骨修复。体内克隆分析表明颅骨在单细胞水平上再生。将 SuSC 植入受伤者体内该部位不仅显示出长期存活，而且还通过直接植入促进骨愈合，其中植入的干细胞产生成骨细胞类型来替代受损组织。新的因此，发现的 SuSC 提供了一个绝佳的机会来获得对病因学的新见解颅缝早闭。在本提案中，我们通过检查 SuSC 的对颅骨健康发育和稳态至关重要的调节。我们将专注于阐明颅缝早闭的分子和细胞机制 SuSC。