PDLIM3-Cholesterol-SMO轴调控SHH通路激活及其在髓母细胞瘤中的功能研究

髓母细胞瘤（medulloblastoma, MB）是最常见的儿童恶性脑肿瘤，主要的治疗手段包括手术及放化疗。虽然近年来MB总体生存率有所提高，但复发、耐药以及长期的慢性损伤仍然存在，因此亟需寻找新的治疗靶点来开发高效低毒的治疗手段。我们通过对不同亚型的MB患者的样本进行GSVA(Gene Set Variation Analysis)分析发现SHH型MB中PDLIM3差异表达显著高于其他亚型，预实验进一步发现PDLIM3对SHH通路具有调控作用，我们推测这种调控作用可能通过PDLIM3募集胆固醇传递给SMO来完成的。本课题我们将探索PDLIM3调控SHH通路的具体机制；用CRISPR技术在MB转基因小鼠模型中敲除PDLIM3探索其在肿瘤发生发展中的作用,此研究将为开发针对PDLIM3为新靶点的抗肿瘤药物提供理论基础和实验依据。

Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite current treatments include surgery, craniospinal radiation and chemotherapy, the patients with MB still succumb to this disease and the survives often suffer from severe advise effects. By GSVA(Gene Set Variation Analysis) with different type of MB patients samples, we previously found that PDLIM3 was always up-regulated in sonic hedgehog (shh) pathway associated MB, while the role of PDLIM3 in the tumoirgenesis of MB remains unknown.  Also, PDLIM3 highly expressed in SHH-MB mouse model derived tumor cells compared with the healthy counterparts. Furthermore our preliminary data show that PDLIM3 positively regulates shh pathway activation which targeting on the process between PTCH and SMO . And knock down of PDLIM3 impacts MB tumor cell proliferation in vitro. In this study, we will further investigate the mechanism by which PDLIM3 regulates shh signaling, moreover, we will determine the functions of PDLIM3 in the initiation and progression of MB by utilizing a MB mouse model. Our studies could shed light on the molecular basis for MB formation, pave the road for developing improved strategies to treat MB.