Ack1介导的PDGFR-AKT信号在神经胶质瘤发生发展中的功能及相关机制研究

Abnormal activation of PDGF-PDGFR signaling plays an important role in the Glioma tumorigenesis. Non-receptor tyrosine kinase Ack1 is one of the most important effectors downstream of PDGFR. However,its function in the tumorigenecity of glioma is not clear. In our preliminary study, we found that ①the expression of Ack1 was up-regulated in the clinical samples of glioma.②Moreover,Ack1 could promote the growth of glioma cells in vitro and in vivo. In the further mechanism study,we found that ③Ack1 was phosphorylated by PDGFR and the phosphorylation was essential for the activation of PDGF-PDGFR-AKT signaling.So,in current study,by using the technologies combining cell biology, molecular biology and animal model,we will systematically ⑴investigate the expression of Ack1 in the clinical glioma samples and analyze the correlation between the expression of Ack1 and the clinical features;⑵further explore the biological signifance and molecular mechanism for the phosphorylation of Ack1 by PDGFR;⑶demonstrate the molecular mechanism of Ack1 activating PDGF-PDGFR-AKT signaling;⑷as well as study the biological function of Ack1 in glioma using animal model.Our study will surely broaden our knowledge about glioma pathogenesis and provide new therapeutic target for the giloma.

PDGF-PDGFR信号异常活化在神经胶质瘤的发生发展中起着重要作用。非受体酪氨酸激酶Ack1作为PDGFR下游重要的效应分子之一，在神经胶质瘤发生发展中的功能尚不清楚。我们前期研究发现:①Ack1在神经胶质瘤样品中表达上调；②Ack1显著促进神经胶质瘤细胞的生长和体内成瘤能力； ③Ack1被PDGFR磷酸化，且Ack1是PDGF-PDGFR-AKT信号活化所必需的。基于这些前期发现，在本研究中我们将利用细胞生物学、分子生物学和动物模型等技术：⑴深入研究Ack1在神经胶质瘤样品中的表达情况，分析其表达与病人临床参数之间的相关性；⑵进一步探索PDGFR 对Ack1进行磷酸化修饰的机制和意义；⑶阐明Ack1调控PDGF-PDGFR-AKT信号的分子机制；⑷利用动物模型在体探索Ack1在神经胶质瘤发生发展中的功能。本项目的研究结果将加深对神经胶质瘤发病机制的认识，为神经胶质瘤的治疗提供新的靶点。

PDGF-PDGFR信号异常活化在神经胶质瘤的发生发展中起着重要作用。非受体酪氨酸激酶Ack1作为PDGFR下游重要的效应分子之一，在神经胶质瘤发生发展中的功能尚不清楚。我们前期研究发现:①Ack1在神经胶质瘤样品中表达上调；②Ack1显著促进神经胶质瘤细胞的生长和体内成瘤能力； ③Ack1被PDGFR磷酸化，且Ack1是PDGF-PDGFR-AKT信号活化所必需的。基于这些前期发现，在本研究中我们将利用细胞生物学、分子生物学和动物模型等技术：⑴深入研究Ack1在神经胶质瘤样品中的表达情况，分析其表达与病人临床参数之间的相关性；⑵进一步探索PDGFR 对Ack1进行磷酸化修饰的机制和意义；⑶阐明Ack1调控PDGF-PDGFR-AKT信号的分子机制；⑷利用动物模型在体探索Ack1在神经胶质瘤发生发展中的功能。本项目的研究结果将加深对神经胶质瘤发病机制的认识，为神经胶质瘤的治疗提供新的靶点。