人体甲状旁腺激素1受体（PTH1R）基因功能缺失引起原发性牙萌出障碍，患牙表现为萌出动力不足。牙基底部骨形成是萌出动力的主要来源之一，但其调控机制尚不清楚。申请人构建了颌骨骨髓间充质干细胞（OMSC）特异性PTH1R敲除鼠，发现突变鼠牙萌出障碍，牙基底部骨形成下降导致萌出动力不足。锌指蛋白467（Zfp467）是PTH1R通路下游因子，但在OMSC与牙萌出中的作用鲜有报道。申请人发现Zfp467受PTH负调控，随牙萌出及成骨分化表达下调，PTH1R敲除导致牙槽骨Zfp467表达增加。本项目拟根据前期结果，通过慢病毒介导的Zfp467表达改变分析其在OMSC成骨分化中的作用，通过ChIP-Seq技术筛选Zfp467下游靶基因，利用CRISPR/Cas9构建Zfp467条件敲除鼠阐明PTH1R/Zfp467信号轴调控牙萌出动力的机制，为探索通过重建萌出动力治疗牙萌出异常的新干预靶点提供线索。

Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene were shown to be associated with primary failure of tooth eruption. The tooth fails to erupt to the occlusal plane due to lack of motive force. Alveolar bone formation at the base of the tooth is required for eruption by providing motive force, whereas the underlying mechanism was not well-understood. We have previously generated orofacial bone marrow stem cells (OMSC) specific deletion of PTH1R mouse model. The mutant mice exhibited disturbance of tooth eruption, accompanied by significantly reduced alveolar bone formation at the base of the tooth when compared to control littermates. The expression of a novel PTH1R signaling downstream factor, Zinc finger protein 467 (Zfp467) was statistically reduced during tooth eruption. PTH directly down-regulated Zfp467 while Zfp467 expression was increased in alveolar bone of mutant mice devoid of PTH1R expression. The potential role of PTH1R/Zfp467 signaling in OMSC during tooth eruption has yet not been investigated. To address these questions, the current study aims at understanding the mechanism of Zfp467 in regulating osteogenesis of OMSC using RNA interference and ChIP-Seq techniques. Zfp467 flox mice will be generated via CRISPR/Cas9-mediated genome editing technology to further elucidate the in vivo function of PTH1R/Zfp467 signaling in bone remodeling during tooth eruption. The results will provide a potential treatment target to control bone formation in patients with disturbances of tooth eruption.