锌指蛋白引导PTCH1蛋白对牙源性角化囊肿病变细胞靶向干预的研究

牙源性角化囊肿（OKC）是一种常见的颌骨牙源性病损，具有较高的生长潜能和明显的复发倾向，可单发，也可伴发痣样基底细胞癌综合征（NBCCS）。约80% OKC（含NBCCS相关性和散发性病变）携带PTCH1基因突变，提示PTCH1基因功能失活及其所致的Sonic Hedgehog（SHH）信号通路异常激活，与OKC发病密切相关。近年SHH通路小分子抑制剂已用于靶向治疗NBCCS相关的OKC及皮肤基底细胞癌，但部分患者因药物靶点基因突变导致耐药和肿瘤复发。因此，本课题拟构建细胞穿膜肽锌指蛋白介导的PTCH1融合蛋白（ZFP-PTCH1），将活性PTCH1蛋白引入OKC病变细胞中，观测ZFP-PTCH1对SHH通路的抑制作用和阻断情况，以及对OKC病变细胞生物学行为的影响，为探索OKC分子靶向治疗新方法提供实验依据。

Odontogenic keratocysts (OKCs) are relatively common lesions in the jaws with an intrinsic higher growth potential and proclivity for recurrence. They could occur sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). Approximately 80% of cases (including NBCCS-related and sporadic lesions) carried PTCH1 mutations, suggesting that mutational inactivation of PTCH1 gene and the aberrant activation of sonic hedgehog signaling pathway might play a significant role in the pathogenesis of OKCs. Recently, SHH pathway inhibitors have provided new treatment strategies for patients with NBCCS-related OKC and basal cell carcinoma, whereas some patients experienced drug resistance and tumor recurrence because of target gene mutations. Thus, we intend to construct a recombinant zinc finger protein-PTCH1 protein (ZFP-PTCH1), which would be internalized into lesion cells, and test for its effect on blocking SHH signal pathway and biological behavior of lesion cells in OKCs. The study intends to explore a new option for molecule-targeted therapy of OKCs.