Mechanism of regulation of progenitor proliferation and transformation

祖细胞增殖和转化的调控机制

• 批准号: 9769907
• 负责人: Peter Canoll
• 金额: $ 17.41万
• 依托单位: ADVANCED SCIENCE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769907
• 关键词: 3-Dimensional; Ablation; Acetylation; Address; Adult; Arginine; Behavioral; Binding; Brain Neoplasms; Cell Cycle; Cell Line; Cells; Complex; Cultured Cells; Data; Data Set; Deposition; Development; E2F1 gene; Enzymes; Epigenetic Process; Event; Expression Profiling; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Glioblastoma; Glioma; Goals; Grant; Histone H3; Histone H4; Histones; Homeostasis; Human; In Vitro; Knowledge; Light; Lysine; Maintenance; Maps; Mediating; Mental disorders; Methylation; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Mutate; Mutation; Myelin; Neurologic; Oligodendroglia; Pathologic; Patients; Pattern; Pharmacology; Physiological; Population; Population Dynamics; Post-Translational Protein Processing; Primary Brain Neoplasms; Process; Proliferating; Protein p53; Proteins; Proteomics; Regulation; Role; Specificity; Specimen; Stem cells; TP53 gene; Testing; Therapeutic; Time; Transcription Coactivator; Tumor Cell Line; base; brain cell; defined contribution; epigenome; experimental study; extracellular; genome sequencing; genome-wide; histone modification; in vivo; knock-down; loss of function; myelination; new therapeutic target; novel; oligodendrocyte lineage; oligodendrocyte progenitor; overexpression; progenitor; response; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics; tumor initiation; whole genome

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.

胶质母细胞瘤（GBM）是高度侵袭性和不可治愈的原发性脑肿瘤， 一年多数百例人脑胶质瘤的表达谱分析和全基因组测序 标本揭示了广泛的遗传变异，并确定了四个主要表达 特征，包括在少突胶质细胞谱系基因中高度富集的表达模式， 其特征还在于肿瘤抑制基因p53的突变。在上一个融资期，我们专注于 关于调节少突胶质细胞祖细胞增殖和基因表达的分子机制， 强调E2F1和Myc作为赖氨酸表观遗传调节因子的转录因子和募集因子 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 PRMT5催化的甲基化），我们将其定义为对少突胶质细胞祖细胞（OPC）至关重要 分化由于PRMT5在神经胶质瘤中上调，并且其表达水平与神经胶质瘤的发病率呈负相关。 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 我们认为，更好地了解其分子作用机制将对我们的工作产生重要影响。 阐明了OPC在生理条件下分化和转化为前神经元的机制 神经胶质瘤我们预计，拟议的实验计划的结果将提高目前的知识 OPC群体动态，同时影响更好地理解神经胶质转化的过程， 提示了新的治疗靶点。总体目标是表征PRMT5分子伴侣， 生理条件下正常OPCs和不同条件下转化OPCs的作用机制 神经胶质瘤进展的阶段，解决其在存在或不存在p53的功能，并评估其潜在的 PRMT5抑制在胶质瘤中的治疗价值。