There and Back Again: Epigenetic Reinforcement of Cellular Signaling States - Overall

来来回回：细胞信号状态的表观遗传强化——总体

• 批准号: 9321069
• 负责人: Jacob David Jaffe
• 金额: $ 148.43万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321069
• 关键词: Algorithms; Architecture; Area; Back; Biological; Biological Assay; Biological Models; Cancer Etiology; Cell Differentiation process; Cell model; Cells; Collaborations; Communities; Consumption; Data; Data Analyses; Development; Disease; Drug resistance; Ensure; Epigenetic Process; Etiology; Event; Gene Silencing; Generations; Genetic; Genetic Transcription; Goals; Institutes; Laboratories; Learning; Libraries; Mass Spectrum Analysis; Mediating; Metadata; Modality; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Network-based; Neurons; Output; Pathway interactions; Phosphorylation; Proteomics; Psychological reinforcement; Reagent; Research Infrastructure; Research Personnel; Resources; Signal Transduction; Source; Stream; System; Techniques; Technology; Testing; Time; United States National Institutes of Health; Vision; Work; base; biological systems; chromatin modification; crowdsourcing; data management; data mining; data resource; drug mechanism; epigenomics; experimental study; genetic profiling; histone modification; human embryonic stem cell; improved; innovation; metaplastic cell transformation; new therapeutic target; next generation; novel; novel therapeutic intervention; novel therapeutics; organizational structure; outreach; phosphoproteomics; programs; prospective; proteomic signature; public health relevance; relating to nervous system; resistance mechanism; response; small molecule; synergism; tool

DESCRIPTION (provided by applicant): The overarching goal of this project is to test the hypothesis that modulation of phosphorylation-mediated signaling events in response to perturbations can establish new cellular states by altering their epigenetic landscapes. To achieve this goal, we propose performing mass spectrometry (MS)-based proteomic assays that specifically target quantitative readouts of phosphosignaling and chromatin modifications in cells on > 15,000 perturbational conditions. These perturbations will focus on modulation of signaling cascades and epigenetic marks by small molecules and gene inactivations. We will study several different cellular model systems, including comprehensive studies neuronal lineage differentiation starting from human embryonic stem cells. We propose to establish a center in order to develop the necessary infrastructure, pipelines, data management, and analytics required to perform what would be the largest set of related experiments with MS proteomic read outs to date. We will also explore next-generation MS acquisition technologies to establish a permanently minable MS data resource that will be accessible to the public. We will contribute the resulting data and tools to the Library of Integrated Network-based Cellular Signatures (LINCS) program for the purpose of making connections among disparate perturbations through phosphoproteomic and chromatin modification signatures in concert with other data types to be contributed to LINCS by other centers. The resulting analyses will help identify novel therapeutic opportunities and synergies, as dysregulation of phosphosignaling and epigenetic systems are two of the most common molecular etiologies identified in a growing number of genetic, developmental, and environmental diseases. In this component of the project description we describe the overall vision for the center, painting in broad strokes our scientific goals, logistcal practices, data analysis strategies, community collaboration plans, and administrative functions.

描述（由申请人提供）：本项目的总体目标是检验以下假设：响应扰动的磷酸化介导的信号传导事件的调节可以通过改变其表观遗传景观来建立新的细胞状态。为了实现这一目标，我们建议进行基于质谱（MS）的蛋白质组学测定，其特异性地靶向在> 15，000个扰动条件下细胞中磷酸化信号传导和染色质修饰的定量读数。这些扰动将集中在小分子和基因失活对信号级联和表观遗传标记的调节上。我们将研究几种不同的细胞模型系统，包括从人胚胎干细胞开始的神经元谱系分化的综合研究。我们建议建立一个中心，以开发必要的基础设施，管道，数据管理和分析，以执行迄今为止最大的MS蛋白质组学读出相关实验。我们还将探索下一代MS采集技术，以建立可供公众访问的永久可开采MS数据资源。我们将把得到的数据和工具贡献给基于集成网络的细胞特征库（LINCS）计划，目的是通过磷酸化蛋白质组学和染色质修饰特征与其他中心贡献给LINCS的其他数据类型相结合，在不同的扰动之间建立联系。由此产生的分析将有助于确定新的治疗机会和协同作用，因为磷酸信号和表观遗传系统的失调是越来越多的遗传，发育和环境疾病中确定的两种最常见的分子病因。 在项目描述的这一部分中，我们描述了中心的总体愿景，概括地描绘了我们的科学目标，逻辑实践，数据分析策略，社区合作计划和行政职能。