Ghrelin调节Wnt/β-catenin 促进中脑神经干细胞定向分化治疗帕金森病的机制研究

Neural stem cells (NSCs) transplantation is widely used in Parkinson’s disease therapy research. However, the main questions of transplanted NSCs are low survival rate and low differentiation rate of dopaminergic neurons (DA neurons). Ghrelin has neuroprotective effect and can enhance neurogenesis in adult. Moreover, another important role of ghrelin in nervous system is to influence the differentiation of DA neurons. Our previous studies showed that ghrelin could enhance the differentiation of midbrain NSCs to DA neurons, and also could up regulate mRNA expressions of Wnt1 and Wnt3a. In order to illustrate the underlying molecular mechanism, in the present study, we detected the differentiation behaviors changes of midbrain NSCs after treated by ghrelin. Meanwhile, the protein expressions changes of Wnt/β-catenin signaling pathway in differentiating DA neurons were detected to reflect the relationship between Wnt and ghrelin. Furthermore, we observed the effect of transplanted midbrain NSCs which induced by ghrelin in PD animal models. This project will investigate the effect of ghrelin on NSCs behaviors and the related mechanism; evaluate the efficacy of ghrelin on NSCs transplantation therapy strategy in PD. We hope that this study could supply some new evidences for NSCs transplantation theory of PD therapy, NSCs induced differentiations and the effect of ghrelin on neuroregeneration.

神经干细胞（NSCs）移植已广泛应用于帕金森病（PD）治疗的研究，但移植的NSCs面临着存活率低和向多巴胺（DA）能神经元分化少的问题。研究发现ghrelin可促进NSCs增殖，影响其向DA能神经元分化，但机制不明。我们前期研究发现ghrelin可提高中脑NSCs向DA能神经元的分化比例，促进Wnt1和Wnt3a的表达。为了研究ghrelin对中脑NSCs向DA能分化的作用机制，本研究利用NSCs培养和细胞移植等方法，在细胞和组织水平观察ghrelin对NSCs向DA能神经元分化程度的影响，检测不同分化时间点，DA能神经元中Wnt1和Wnt3a表达量，及Wnt/β-catenin通路蛋白表达及磷酸化程度；最后将ghrelin基因修饰的NSCs移植于PD动物模型上，观察DA能神经元的存活、DA释放和动物运动行为改善的情况。本项目将为NSCs的定向诱导并移植治疗PD提供一定的实验依据。

Ghrelin对多巴胺（DA）能神经元具有保护作用，研究发现ghrelin可促进NSCs增殖，影响神经元分化，但其对中脑神经干细胞（NSCs）的作用和机制不明。本研究首先观察了ghrelin对中脑NSCs增殖、分化和迁移等生物学行为的影响，发现ghrelin可通过促进中脑NSCs的增殖和向神经元分化等作用促进神经再生。我们也发现ghrelin可促进中脑NSCs向DA能神经元分化，并对其机制进行探讨。本研究观察到ghrelin处理后中脑NSCs 胞内 Wnt1和Wnt3a表达水平增加，并阐明了ghrelin对DA能神经元分化的影响是通过调控Wnt/ß-catenin信号实现。本项目将为NSCs的定向诱导移植治疗PD和ghrelin作为神经保护药物的开发，提供一定的实验依据。