诱导多能干细胞iPS是由体细胞诱导而成的一类具有胚胎干细胞特性的多能干细胞, 建立遗传性疾病特异性iPS细胞模型进而探索致病基因功能和其致病机制是近期国际研究热点。低碱性磷酸酯酶症HPP是由于碱性磷酸酯酶基因ALPL突变导致的骨及牙齿发育缺陷的遗传性疾病， ALPL基因被公认是发育期干细胞生物学标志，其突变是否能影响发育期干细胞行为而导致成骨发育不良未见研究报道。我们前期研究发现HPP患者间充质干细胞成骨分化能力减弱与表观遗传学因子等表达异常相关，建立的HPP疾病iPS细胞也展示异常生物学行为，但其分子致病机制不甚清楚。本项目拟通过建立HPP疾病特异iPS细胞模型，检测疾病iPS细胞生物学行为，分析ALPL功能缺陷对iPS细胞相关生物分子代谢的影响，最后评估疾病iPS细胞成骨分化的表观遗传学调控模式，以期揭示ALPL基因在干细胞分化中的生物学作用，阐明HPP疾病成骨发育不良的分子致病机制。

Induced pluripotent stem cell (iPS) is a type of pluripotent stem cell artificially derived from adult somatic cell by by inducing a forced expression of specific genes, which are similar to natural pluripotent stem cells, such as embryonic stem cells. Modelling pathogenesis of the hereditary disease using patient-specific iPS has recently become a research focus. Hypophosphatasia (HPP) causes the hereditary developmental disorders of bone and teeth due to mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL), and ALPL gene is always acknowleged as the biomarker of stem cells without any functions. Unfortunately, there are no related research reports that ALPL mutation could cause abnormal biological behaviors of stem cells resulting in osteogenesis imperfecta. Our previous research found that the decreasing osteogenic potentials of HPP messenchymal stem cells were related to the changes of genes patterning including epigenetic factors, then HPP-iPS cells also presented abnormal biological characteristics. However , its molecular and pathogenic mechanisms remain unraveled. In our project, we will plan to construct the modelling of the HPP patient-specific iPS, and characterize their biological behaviors change, and then examine the effects of ALPL mutations on cellular metabolisms, finally evaluate the epigenetic regulatory patterns in the osteogenic differentiation of HPP-iPS. We wish to explore the roles of ALPL gene in the differentiation of stem cells, and disclose the pathogenic mechanism of HPP phenotypes-osteogenesis imperfecta.