Mechanism of regulation of progenitor proliferation and transformation

胶质母细胞瘤(GBM)是一种高度侵袭性和不可治愈的原发脑肿瘤，中位存活率很低。 一年多了。数百例人脑胶质瘤的基因表达谱和全基因组测序 样本揭示了广泛的遗传变化，并确定了四种主要的表达 特征，包括高度丰富的少突胶质细胞谱系基因的表达模式，这是 也以肿瘤抑制基因P53的突变为特征。在上一次融资期间，我们专注于 少突胶质前体细胞增殖和基因表达调控的分子机制， 重点介绍了E2F1和Myc作为转录因子和赖氨酸表观遗传调节子的招募 核小体组蛋白H3上的残基。这次更新的重点是一种新的组蛋白修饰(对称精氨酸 由PRMT5催化的甲基化)，我们将其定义为对少突胶质细胞前体细胞(OPC)至关重要 差异化。由于PRMT5在胶质瘤中表达上调，其表达水平与 患者的生存，它代表了一个非常有吸引力的治疗目标。基于我们的蛋白质组和转录组 数据集我们认为，更好地理解其分子作用机制将对 OPC在生理条件下的分化及向原神经细胞转化的机制 神经胶质瘤。我们预计，拟议的试验计划的结果将增强目前的知识 OPC种群动态，同时影响更好地理解胶质细胞转化和 提出了新的治疗靶点。总体目标是表征PRMT5分子伙伴和 生理条件下正常OPC和不同条件下转化OPC的作用机制 胶质瘤进展的分期，在有无P53的情况下讨论其功能，并评估其潜在的 抑制PRMT5在脑胶质瘤中的治疗价值

Glioblastomas (GBM) are highly aggressive and incurable primary brain tumors, with a median survival of little more than a year. Expression profiling and whole genome sequencing from hundreds of human glioma specimens have revealed a broad spectrum of genetic alterations and identified four major expression signatures, including a pattern of expression that is highly enriched in oligodendrocyte lineage genes, which is also characterized by mutations in the tumor suppressor p53. During the previous funding period we focused on the molecular mechanisms regulating proliferation and gene expression in oligodendrocyte progenitor cells, with an emphasis on E2F1 and Myc as transcription factors and recruiters of epigenetic modulators of lysine residues on nucleosomal histone H3. This renewal focuses on a novel histone modification (symmetric arginine methylation catalyzed by PRMT5), which we define as critical for oligodendrocyte progenitor (OPC) differentiation. Since PRMT5 is upregulated in glioma, and its expression levels negatively correlate with patients' survival, it represents a very attractive therapeutic target. Based on our proteomic and transcriptomic datasets we propose that a better understanding of its molecular mechanism of action would shed important light on mechanisms of OPC differentiation in physiological conditions and of transformation into proneural gliomas. We anticipate that the results of the proposed experimental plan will enhance the current knowledge of OPC population dynamic, while impacting a better understanding of the process of glial transformation and suggesting novel therapeutic targets. The overall goal is to characterize PRMT5 molecular partners and mechanism of action in normal OPCs under physiological conditions and in transformed OPCs at different stages of glioma progression, address its function in the presence or absence of p53 and evaluate the potential therapeutic value of PRMT5 inhibition in gliomas.