成纤维细胞生长因子18对成牙本质细胞分化的作用及信号传导通路的研究
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摘要
成牙本质细胞是牙髓-牙本质复合体的特征性细胞，具有高度分化、极性和分泌的特性，是合成和分泌牙本质基质的唯一细胞。成牙本质细胞可以在牙齿发育期间生成牙本质，也是牙齿损伤修复中起主要作用的细胞。成牙本质细胞分化是牙胚发育的重要阶段，也是牙髓组织自身损伤修复过程中的关键环节。这一过程受多种信号分子的调控，从基因表达水平阐明成牙本质细胞分化的调控规律及其影响因素有助于对牙齿发育、损伤与修复等过程的深入认识。
成纤维细胞生长因子18(Fibroblast growth factor 18，FGF18)是1998年发现的成纤维细胞生长因子家族的新成员，与FGF8和FGF17属于同一亚家族。研究证实FGF18是一种发育组织重要的分泌性信号分子，参与多种组织的发育，尤其在外胚层器官比如脑的发育等过程中起了重要作用。在胚胎的骨和软骨中FGF18可通过MAPK信号转导途径调节细胞的发育，FGF18的缺失就会严重影响成骨和软骨的形成。在同样具有矿化能力并且来源于外胚层的牙齿发育过程中，FGF18存在特异的时空分布特点，且随着成牙本质细胞的逐渐分化成熟，自身表达增强，提示FGF18参与成牙本质细胞的分化和牙本质的形成。但FGF18在成牙本质细胞形成和分化过程中起什么作用?通过哪种途径起作用?至今尚不很清楚。本课题对于这些问题进行了较深入的研究。具体内容如下：
Odontoblast is a special type of highly differentiated, tall columnar cell residing in pulp-dentin complex. As it is the only cell that secrete dentin matrix protein, it is in charge of dentin formation during tooth development and post-trauma repairation in postnatal tooth. So it is important to clarify the mechanism of odontoblast differentiation and mineralization, which is governed by a great deal of sequential and reciprocal interactions between epithelial and mesenchymal tissues.
Fibroblast Growth Factor 18(FGF18) is a newly discovered member of FGFs family. Sequence comparison indicates that FGF18 is highly conserved between humans and mice and is most homologous to FGF8 and FGF17 among the FGF family members. It is a unique secreted signaling molecule in several adult and developing tissues and plays a crucial role in development of some ectodermal organs like midbrain. It is also a pleiotropic growth factor that stimulates proliferation in some tissues such as articular cartilage and bone through MAPK signal pathway. In FGF18 knock-out mouse, ossification of long bone and craniofacial bone was delayed, which indicated that FGF18 is a regulatory factor of osteoblast differentiation. It is interesting that FGF18 is expressed in a distinct temporal and spatial pattern during mouse odontogenesis and its expression is upregulated with the differentiation of odontoblasts, which suggests that there is great possibility of FGF18 to participate in the proliferation and differentiation of ondontoblast. Thus, the aim of this study was to investigate the role of FGF18 in regulating the proliferation and differentiation of odontoblast cells and its signal pathway. The present study consists of three parts as follow:
成纤维细胞生长因子18(Fibroblast growth factor 18，FGF18)是1998年发现的成纤维细胞生长因子家族的新成员，与FGF8和FGF17属于同一亚家族。研究证实FGF18是一种发育组织重要的分泌性信号分子，参与多种组织的发育，尤其在外胚层器官比如脑的发育等过程中起了重要作用。在胚胎的骨和软骨中FGF18可通过MAPK信号转导途径调节细胞的发育，FGF18的缺失就会严重影响成骨和软骨的形成。在同样具有矿化能力并且来源于外胚层的牙齿发育过程中，FGF18存在特异的时空分布特点，且随着成牙本质细胞的逐渐分化成熟，自身表达增强，提示FGF18参与成牙本质细胞的分化和牙本质的形成。但FGF18在成牙本质细胞形成和分化过程中起什么作用?通过哪种途径起作用?至今尚不很清楚。本课题对于这些问题进行了较深入的研究。具体内容如下：
Odontoblast is a special type of highly differentiated, tall columnar cell residing in pulp-dentin complex. As it is the only cell that secrete dentin matrix protein, it is in charge of dentin formation during tooth development and post-trauma repairation in postnatal tooth. So it is important to clarify the mechanism of odontoblast differentiation and mineralization, which is governed by a great deal of sequential and reciprocal interactions between epithelial and mesenchymal tissues.
Fibroblast Growth Factor 18(FGF18) is a newly discovered member of FGFs family. Sequence comparison indicates that FGF18 is highly conserved between humans and mice and is most homologous to FGF8 and FGF17 among the FGF family members. It is a unique secreted signaling molecule in several adult and developing tissues and plays a crucial role in development of some ectodermal organs like midbrain. It is also a pleiotropic growth factor that stimulates proliferation in some tissues such as articular cartilage and bone through MAPK signal pathway. In FGF18 knock-out mouse, ossification of long bone and craniofacial bone was delayed, which indicated that FGF18 is a regulatory factor of osteoblast differentiation. It is interesting that FGF18 is expressed in a distinct temporal and spatial pattern during mouse odontogenesis and its expression is upregulated with the differentiation of odontoblasts, which suggests that there is great possibility of FGF18 to participate in the proliferation and differentiation of ondontoblast. Thus, the aim of this study was to investigate the role of FGF18 in regulating the proliferation and differentiation of odontoblast cells and its signal pathway. The present study consists of three parts as follow:
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