受体相互作用蛋白140在干细胞向神经细胞定向分化中的作用及分子机制研究

As a transcriptional regulator, receptor interactor protein 140(RIP140),which localized on chromosome 21, is significantly upregulated in the brain of DS fetus and adult compared with normal ones. Taken with the fact that proliferation and migration of mouse glioma is inhibited by RIP140 overexpression indicate that DS mental retardation might be resulted partially from inhibited proliferation and migration of neural cell by RIP140 overexpression. DS is one of the abnormal developmental disorder，abnormal differentiation stem cells might be the key factors which involved in DS mental retardation. At present, the role of RIP140 in stem cells differentiated into neural cells while interaction between retinoic acid(RA) and RIP140 could induces the directed differentiation of neural cell from stem cells. In this study, embryonic stem cells and neural stem cells derived from DS and its normal control were used as the model to determine how RIP140 affect the differentiation into neural cell by using overexpression and knockdown techniques. furthermore, in vitro differential cell models induced by estrogen, retinoic acid or glucocorticoid were taken together to systemtically to identify the downstreaming signal pathway and effect of RIP140 on stem cell directed differentiation to neural cells and molecular mechanism. All this is great useful to study the biological characteristic of RIP140 andtargeted therapy of DS related mental retardation.

受体相互作用蛋白140（RIP140)是21号染色体上的转录调节相关基因，参与神经系统发育和高级脑功能的调节。课题组前期研究显示，RIP140在大脑发育中具有特定的时空表达模式，在唐氏综合征胎儿和成人脑中的表达明显增高，其过表达可抑制神经细胞的增殖和迁移行为，但是其在干细胞向神经细胞定向分化中的作用尚不清楚。为此本研究拟以正常和唐氏综合征（Down Syndrome，DS）胚胎干细胞神经干细胞为研究对象，采用基因过表达和敲低技术，通过维甲酸、雌激素和糖皮质激素体外定向诱导分化的细胞模型分析RIP140在正常和DS干细胞向神经细胞定向分化中的作用和下游信号通路，明确其作用的分子机制，为理解DS智力低下发生的分子机制和发现潜在的干预靶点奠定理论和实验基础。

受体相互作用蛋白140（RIP140)是21号染色体上的转录调节相关基因，参与神经系统发育和高级脑功能的调节。课题组前期研究显示，RIP140在大脑发育中具有特定的时空表达模式，在唐氏综合征胎儿和成人脑中的表达明显增高，其过表达可抑制神经细胞的增殖和迁移行为，但是其在干细胞向神经细胞定向分化中的作用尚不清楚。为此本研究拟以正常和唐氏综合征（Down Syndrome，DS）胚胎干细胞神经干细胞为研究对象，采用基因过表达和敲低技术，通过维甲酸、雌激素和糖皮质激素体外定向诱导分化的细胞模型分析RIP140在正常和DS干细胞向神经细胞定向分化中的作用和下游信号通路，明确其作用的分子机制，为理解DS智力低下发生的分子机制和发现潜在的干预靶点奠定理论和实验基础。