Characterization of Pathways Controlling Cancer at the Level of Gene Regulation

项目概要-总体 此P01应用程序中的三个项目均得到P01核心的大力支持， 研究领域相关的中心目标的赠款的表征途径控制癌症在 基因调控水平。随着强大的技术的出现，可以在单个细胞中检测基因表达， 在细胞水平上，越来越明显的是，转录状态比细胞水平上的转录状态更具动态性和异质性。 以前相信。正常细胞如此，癌细胞更是如此。这三个项目 P01从不同的角度和互补的实验系统来解决这个问题。的 这项研究的成果有望更好地理解转录异质性如何控制 细胞状态的可塑性，包括分化状态，细胞从正常发展到恶性。 在项目1中，Jacks实验室将在小鼠肿瘤进展的背景下探索这个问题。 肺腺癌模型。这些研究将研究这种异质性如何随着时间的推移而演变， 控制观察到的变化和转录网络，以及对癌症的免疫反应如何影响 这些过程。转录异质性的主题也将由Lees实验室在2010年进行探索。 项目3使用相同的模型系统。项目3将关注PRC1突变的影响， 在这些过程中，Bmi1组分。作为项目2的一部分，夏普实验室将探索miRNAs的作用， 在基因表达的调控中，重点是miRNAs如何控制基因表达模式， 在单细胞水平表达并建立不同的细胞状态。这项研究将有助于分析 项目1和项目3中生成的数据。Aviv Regev博士（布罗德研究所和麻省理工学院） 与此主题相关的研究。P01核心提供的专家生物信息学支持也是一个 这是这项研究工作的重要组成部分。项目2还将探索新的基因表达模型 涉及转录起始位点和增强子元件的凝胶-溶胶转换，这有助于解释 基因表达的动态性质以及转录控制的其他方面。第二个主题是 计划是检查癌症干细胞样和龛样细胞的发展以及其他影响 对肿瘤进展过程中细胞分化的影响。项目1和项目3都将探讨这一主题。在 除了其他方面，P01核心将是必不可少的研究，检查这些发现的相关性， 人类癌症最后一个主题涉及到细胞和分子的影响，抑制的审查， 表观遗传调节因子PRMT5，其作为参与mRNA的Sm蛋白的精氨酸二甲基酶发挥作用 拼接项目2和3将合作研究PRMT5抑制的生物学和生物化学， 开发用于治疗人类癌症的新抗癌剂的最终目标，包括 胶质母细胞瘤和肺癌。

Project Summary – Overall The three Projects in this P01 application, all strongly supported by the P01 Core, address overlapping research areas related to the central goals of the grant of characterizing pathways controlling cancer at the level of gene regulation. With the advent of powerful technologies to examine gene expression at the single cell level, it is becoming apparent that transcriptional states are much more dynamic and heterogeneous than previously believed. This is true of normal cells and, even more so, in cancer cells. The three Projects in this P01 address this question from a variety of perspectives and with complementary experimental systems. The product of this research is expected to be a greater understanding of how transcriptional heterogeneity governs the plasticity of cellular states, including differentiation states, as cells progress from normalcy to malignancy. In Project 1, the Jacks laboratory will explore this question in the context of tumor progression in mouse models of lung adenocarcinoma. These studies will examine how such heterogeneity evolves over time, what controls the observed changes and transcriptional networks as well as how immune responses to cancer affect these processes. The theme of transcriptional heterogeneity will also be explored by the Lees laboratory in Project 3 using the same model systems. Project 3 will focus on the effects of mutation of the PRC1 component Bmi1 in these processes. As part of Project 2, the Sharp laboratory will explore the role of miRNAs in the regulation of gene expression, with a focus on how miRNAs function to control patterns of gene expression at the single cell level and establish distinct cellular states. This research will inform the analysis of data generated in Projects 1 and 3. Dr. Aviv Regev (Broad Institute and MIT) is an important collaborator on the research related to this theme. The expert bioinformatics support provided by the P01 Core is also an essential component of this research effort. Project 2 will also explore novel models of gene expression involving gel-sol transitions at transcription start sites and enhancer element, which could help explain the dynamic nature of gene expression as well as other aspects of transcriptional control. A second theme of the Program is the examination of the development of cancer stem-like and niche-like cells as well as other effects on cellular differentiation during tumor progression. This theme will be pursued by both Projects 1 and 3. In addition to other aspects, the P01 Core will be essential for studies examining the relevance of these finding to human cancer. The final theme concerns the examination of the cellular and molecular effects of inhibition of the epigenetic regulator PRMT5, which functions as an argenine dimethylase of Sm proteins involved in mRNA splicing. Projects 2 and 3 will collaborate on the study of the biology and biochemistry of PRMT5 inhibition with the ultimate goal of developing new anti-cancer agents for the treatment of human cancers, including glioblastoma and lung cancer.