CMA通过N-CoR/UPR通路对胶质母细胞瘤凋亡的调控作用及其机制研究

项目名称： CMA通过N-CoR/UPR通路对胶质母细胞瘤凋亡的调控作用及其机制研究

项目编号： No.81502139

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王勇杰

作者单位： 浙江大学

项目金额： 18万元

中文摘要： 胶质母细胞瘤（GBM）是最常见的原发颅内恶性肿瘤，关于其发生发展的调控机制仍不十分清楚。分子伴侣介导的自噬（CMA）是溶酶体依赖的选择性蛋白降解途径，在多种肿瘤中起自我保护作用，但未报道与GBM发生发展的关系。N-CoR是细胞核抑制性蛋白复合体的关键成分，在细胞中被CMA识别而降解，其在细胞质中堆积可继发未折叠蛋白应答（UPR）致细胞凋亡。CMA关键组成蛋白LAMP-2A表达水平特异性地反映CMA激活水平。我们前期研究发现，在GBM中LAMP-2A表达水平显著升高，siRNA抑制其表达，发现N-CoR在细胞中堆积，细胞凋亡水平明显上调。推测CMA在GBM中被激活，通过降解N-CoR，下调UPR，避免细胞凋亡。因此我们将围绕CMA/N-CoR/UPR通路，采用慢病毒、立体定向注射、免疫印迹等技术，从体内、体外层面，阐明CMA对GBM凋亡的调控作用和机制，为治疗GBM探索新方法和潜在干预靶点。

中文关键词： 胶质母细胞瘤；分子伴侣介导的自噬；核受体共阻遏物；未折叠蛋白应答；凋亡

英文摘要： Glioblastoma (GBM) is the most common primary intracranial malignant tumor. The upstream tumorigenic mechanism still remains unclear. As the lysosome-dependent selective protein degradation pathway, chaperone mediated autophagy (CMA) provide shelter for various types of tumors. But its role in GBM development still remains uncovered. As the key component of the inhibitive protein complex, N-CoR is recognized and degraded selectively by CMA, while its accumulation in cytoplasm can excite unfolded protein response (UPR) and lead to cell apoptosis. It has been verified that the expression of key protein LAMP-2A reflects the CMA activity specifically. Our previous study demonstrated a significantly elevated LAMP-2A expression in GBM compared to normal brain tissue, and after siRNA mediated knock-down of LAMP-2A, N-CoR accumulation and increased apoptosis were observed. Therefore we hypothesize that CMA is activated in GBM and protects tumor cells against apoptosis via degradation of N-CoR, which results in reduced UPR. Taken together, we will center upon CMA/N-CoR/UPR pathway to investigate the regulatory effect of CMA on GBM apoptosis and unveil the molecular mechanism behind both in vitro and in vivo, with the help of various techniques including lenti-virus, stereotaxic injection, western-blot, et al.. As a result, we hope to provide potential target for GBM treatment in the future.

英文关键词： glioblastoma;chaperone-mediated autophagy;nuclear receptor co-repressor;unfolded protein response;apoptosis