Investigations of Cryab activity in gliomagenesis

描述(由申请者提供)：高级别胶质瘤预后不佳。目前的治疗方法只能适度延长生存期，因此人们对开发更好的、有针对性的治疗胶质瘤的方法非常感兴趣。由于CryAB基因在人脑胶质瘤中经常过度表达，已被认为是胶质瘤的候选癌基因。在已建立的胶质瘤细胞系中的研究表明，CryAB在细胞凋亡和侵袭中发挥了作用，但由于缺乏动物研究，也可以模拟CryAB对免疫系统的潜在影响，因此CryAB在胶质瘤发生和发展中的重要性尚不清楚。本文提出的研究将利用小鼠遗传模型，在体内、免疫活性和本土环境中调查CryAB对胶质瘤形成的影响。具体地说，我们将研究在胶质瘤易患的遗传背景下，基因CryAB的过度表达和缺失对胶质瘤形成的影响。我们将检测CryAB过表达对体内细胞凋亡率和免疫细胞浸润的影响。这些研究有望确定CryAB在胶质瘤形成中的致癌作用，并为未来确定调节CryAB的药物是否具有脑胶质瘤靶向治疗作用提供基础。

DESCRIPTION (provided by applicant): High-grade gliomas carry a grim prognosis. Current therapies only modestly prolong survival and therefore there is great interest in developing better, targeted therapies for glioma treatment. CRYAB has been identified as a candidate glioma oncogene as it is frequently over-expressed in human gliomas. Studies in established glioma cell lines have indicated a role for CRYAB in apoptosis and invasion, however the importance of CRYAB in glioma initiation and progression remains unclear due to a paucity of animal studies where potential effects of CRYAB on the immune system can also be modeled. The research proposed here will utilize mouse genetic models to investigate the impact of Cryab on gliomagenesis in an in vivo, immunocompetent, autochthonous setting. Specifically, the impact of genetic Cryab over-expression and loss on glioma formation in a glioma pre-disposed genetic background will be examined. The effect of Cryab over-expression on apoptosis rates and immune cell infiltration in vivo will be examined. These studies are expected to establish an oncogenic role of CRYAB in gliomagenesis and to provide the foundation for future studies to determine if CRYAB-modulating drugs may have utility as glioma targeted therapies.