牙源性上皮细胞中PTCH1的体内功能研究

Odontogenic epithelium is a kind of epithelium that possesses the potential of developing into dental tissues and plays an important role in all stages of tooth development. When the tooth finished development, the odontogenic epithelium keeps in a static form in the mandible. Previous studies have shown that in the process of dental development, the odontogenic epithelium can express a variety of Sonic Hedgehog (SHH) signaling pathway-related molecules, and a variety of jaw cyst and odontogenic tumor epithelium harbor SHH signaling pathway-related molecular mutations , but the regulation mechanism is not clear. In this study, we disrupted PTCH1 specifically from the odontogenic epithelial cells to observe the development of teeth as well as the periodontal tissues in conditional knockout (cKO) mice. At the same time, we supposed the cKO mice will develop jaw cysts or odontogenic tumors. Next, we try to use the SHH signaling inhibitors like GDC-0449 to treat and prevent the occurrence of jaw cysts or odontogenic tumors. We hope this study can provide more therapeutic methods for the treatment of dental cysts and odontogenic tumors.

牙源性上皮是具有发育成牙体组织潜能的上皮，在牙发育各个时期均具有重要作用，其在发育完成后的稳态维持也是非常值得关注的科学问题。以往研究显示，在牙发育过程中，牙源性上皮可表达多种Sonic Hedgehog (SHH)信号通路相关分子，而多种颌骨囊肿和牙源性肿瘤上皮中也存在SHH信号通路相关分子的突变，但体内调控机制并不明确。本课题拟建立在牙源性上皮细胞中特异性敲除PTCH1的条件性基因敲除小鼠，观察分析敲除小鼠的牙及周围支持组织发育，以及后期可能会形成的颌骨囊肿或牙源性肿瘤，并提出可能的作用机制。随后，通过体内给药的方法，观察分析以GDC-0449为代表的SHH信号通路抑制剂对颌骨囊肿或牙源性肿瘤的治疗和预防效果，深入研究PTCH1介导的SHH信号通路在牙源性上皮细胞中的功能作用以及探索应用SHH信号通路抑制剂用于靶向治疗颌骨囊肿或牙源性肿瘤的可能性。

先前的研究表明多种牙源性肿瘤可携带PTCH1的基因突变，患者可伴发一定程度牙发育畸形和多生牙等临床表现。但PTCH1突变和牙发育畸形以及牙源性肿瘤发生之间的关系并不明确。本课题通过在前成牙本质细胞（牙源性间充质细胞来源）中敲除PTCH1基因，探究牙源性间充质细胞中PTCH1的体内功能，尝试构建牙发育缺陷和牙源性肿瘤的疾病模型。通过分析疾病表型，探讨疾病的发生机制以及为疾病治疗和再生牙研究提供理论基础。课题同时着眼于临床研究，1）明确BRAF p.V600E突变在牙源性角化囊肿中罕发，解决关于其突变频发和少发的争论；2）明确实性牙源性角化囊肿和角化型成釉细胞瘤为同一类型疾病，解决其临床分类难的问题。

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