Genetic Regulatory Network in Craniofacial Development

颅面发育中的遗传调控网络

• 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
• 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

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 颅面发育的遗传调控网络 摘要 这项建议继续我们的努力，以破译骨骼的信号网络背后的颅面 发展和疾病。颅面骨骼由脏颅和脑颅组成， 再分为头盖骨和软骨头盖骨。在颅骨发育过程中，颅缝 作为骨骼生成的生长中心。缝线形态发生缺陷导致过早闭合 颅缝早闭症是一种毁灭性的儿童疾病，约2,500人中就有1人患病。虽然人类基因 分析已经确定了与发病机制相关的基因，但对缝合的调控知之甚少。 闭合对于健康头骨的发育至关重要。在先前提出的调查中，我们 阐明了Axin 2通过调节Wnt调节缝线形态发生的机制， 下游信号通路。BMP和FGF信号传导的串扰在Wnt介导的细胞凋亡中起着关键作用。 颅面骨发育此外，存在于缝间充质中的骨骼干细胞已经被 在我们的实验室里成功地鉴定和分离出来。这种缝线干细胞（SuSC）群体负责 婴儿的颅骨发育以及成人的体内平衡维持。一旦受伤，休眠 SuSCs反应迅速，并以细胞自主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再生。将SuSCs植入受伤者 该部位不仅显示出长期存活，而且通过直接植入促进骨愈合， 植入的干细胞产生替代受损组织的成骨细胞类型。新 因此，发现的SuSCs提供了一个极好的机会，以获得新的见解的病因学， 颅缝早闭在本提案中，我们继续深入评估南苏丹供应链， 调节对颅骨的健康发育和内环境稳定至关重要。我们将集中于 阐明了由神经元调节异常引起的颅缝早闭症的分子和细胞机制， SUSC。