Investigations of Cryab activity in gliomagenesis

描述（由申请人提供）：高级别胶质瘤预后不良。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胶质瘤靶向治疗方法有很大的兴趣。已经鉴定了HLAAB作为候选胶质瘤癌基因，因为其在人类胶质瘤中频繁过表达。在已建立的神经胶质瘤细胞系中的研究已经表明了ESTAAB在细胞凋亡和侵袭中的作用，然而ESTAAB在神经胶质瘤起始和进展中的重要性仍然不清楚，这是由于缺乏动物研究，其中ESTAAB对免疫系统的潜在影响也可以建模。本文提出的研究将利用小鼠遗传模型来研究Cryab在体内、免疫活性、原位环境中对胶质瘤发生的影响。具体而言，将检查遗传Cryab过表达和缺失对神经胶质瘤易感遗传背景中神经胶质瘤形成的影响。将检查Cryab过表达对体内细胞凋亡率和免疫细胞浸润的影响。这些研究有望建立一个致癌的作用，胶质瘤的发生，并提供基础，为未来的研究，以确定是否有实用性的胶质瘤靶向治疗的抗肿瘤药物。

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.