Wip1对胚胎干细胞自我更新、分化与致瘤性的作用及其分子机制研究

项目名称： Wip1对胚胎干细胞自我更新、分化与致瘤性的作用及其分子机制研究

项目编号： No.31460314

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 发育生物学与生殖生物学

项目作者： 王淑芬

作者单位： 昆明医科大学

项目金额： 50万元

中文摘要： 干细胞治疗为目前一些难以医治的疑难疾病治疗带来希望，但在其临床应用之前，必须解决干细胞致瘤性的安全问题。Wipl是一个新型的原癌基因，对正常的生理功能也起着重要的调控作用，参与调控神经干细胞及骨髓干细胞的自我更新及分化，但对多潜能干细胞的作用及其调控机理并不清楚。本项目拟利用Wipl缺陷小鼠建立Wipl缺陷型及野生型多潜能胚胎干细胞系；研究Wipl对胚胎干细胞的自我更新、神经分化及致瘤性的作用，并探讨其调控的分子机制，揭示Wipl调控网络的关键分子；解析抑制或激活这些调控关键分子能否改善多潜能干细胞的自我更新及神经分化，能否避免分化过程中分化细胞转变为肿瘤细胞，并降低移植细胞在动物模型体内的致瘤性，从而使干细胞治疗成为可能。通过此研究，可为认识多潜能干细胞自我更新、分化及致瘤性的分子机理提供科学证据，对解决多潜能干细胞的致瘤性问题及理解肿瘤的发病机理具有重要的理论与临床实践意义。

中文关键词： 小鼠胚胎干细胞；自我更新；定向分化；多能性；信号通路

英文摘要： Stem cell therapy has the potential to cure many human uncurable diseases. However, the tumorigenesis characterization of pluripotent stem cell must be resolved before the clinical application. An understanding of the role of Wip1 in self-renewal,differentiation and tumorigenesis of pluripotent embryonic stem cells (ESC) and their regulatory mechanism is critical as this could lead to resolving the problem of tumorigenesis in stem cells and dissecting the pathogenesis of cancers. Based on the latest report that Wip1 is a new type of oncogene and plays a positive role in the proliferation capacity of neural stem cells and mesenchymal stem cells. But the role of Wip1 in pluripotent stem cell and their regulatory mechanisms remain unkown. With the application of Wip1 knockout mice, we will establish the ESC lines of Wip1 knockout and wildtype; To explore the effect of Wip1 on self-renewal,neural differentiation and tumorigenesis in ESC; To decipher the molecular mechnisms of these regulatory effect and uncover the key regulators in the Wip1 regulatory network; To better the self-renewal or neural differentiation of ESC with small molecule agonists or antagonsits of these key regulators, which avoid the transformation of differentiating stem cells to cancerous stem cells as well as decrease the possibility of tumorigenesis after stem cells or their differentiated cells were transplantation into animal disease models,result in the successful clinical application of stem cells without tumorigenesis and the final therapy of the uncurable diseases.

英文关键词： MouseESC;Self-renewal;Directed differetiation;Pluripotency;Signal pathway