TAp63α对BMP9诱导的成骨分化的调节及其机制的研究

Congenital limb malformations is one of the common deformities in clinical practice,the research on its prevention and treatment is very hot currently.Recent studies showed that heterozygous germline mutations in p63 result in a plethora of human syndromes involving defective development of the limbs.p63 can interact with BMPs to regulate the development of ectodermal organs. Our lab previously demonstrated that BMP9 is one of the most potent osteogenic BMPs and found TAp63α can up-regulate the expression of BMP9 in mesenchymal stem cells .In this project we overexpress TAp63α、ΔNp63α and BMP9 simultaneously or respectively in immortalized mouse embryonic fibroblasts (iMEFs) firstly,then investigate if there is a crosstalk between BMP9 and p63 through ChIP assay, investigate the effect of TAp63α and ΔNp63α on BMP9-induced osteogenic differentiation of mesenchymal stem cells by several molecular biological techniques to address the question that if p63 can regulate BMP9- induced osteogenic differentiation and the detailed mechanism involved in the regulatory of p63 on bone’s development . Ultimately, this knowledge would help us to combat bone disorders, such as developmental deformity and bone regeneration.

新生儿先天性肢体畸形是临床上常见畸形之一，其预防和治疗是目前研究的热点。研究发现p63基因的缺失能够导致严重的肢体发育缺陷，并且能够与骨形态发生蛋白（BMPs）信号分子相互作用来调控外胚层器官的生长发育。本课题组在前期工作中已发现BMP9是目前所发现的BMPs中具有最强诱导间充质干细胞成骨分化的骨形态发生蛋白，并且发现TAp63α对BMP9的表达具有促进作用。因此本项目拟在永生化的小鼠胚胎成纤维细胞（iMEFs）中分别或同时过表达TAp63α、ΔNp63α和BMP9，利用染色质共沉淀方法，验证p63和BMP9的相互关系，并采用分子生物学技术检测TAp63α和ΔNp63α对BMP9诱导的早、晚期成骨指标以及体内异位成骨的影响，探讨p63对BMP9所诱导间充质干细胞成骨分化的影响，从而阐明p63在骨发育中可能存在的分子机制，为新生儿肢体畸形预防和基因治疗提供新的靶点。

新生儿先天性肢体畸形是临床上常见畸形之一，其预防和治疗是目前研究的热点。研究发现p63基因的缺失能够导致严重的肢体发育缺陷，并且能够与骨形态发生蛋白（BMPs）信号分子相互作用来调控外胚层器官的生长发育。该项目通过研究TAp63基因在BMP-9诱导小鼠胚胎成纤维细胞成骨分化以及异位骨化中的作用机制发现p63可调控在BMP9促进小鼠胚胎成纤维细胞成骨分化,首次探讨了p63与BMP9的相互作用及其作用机制，对p63基因缺失相关疾病提供了新的基因治疗的靶点。