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: 8787825
• 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/8787825
• 关键词: Algorithms; Architecture; Area; Back; Biological; Biological Assay; Biological Models; Cancer Etiology; Cell Differentiation process; Cell model; Cells; Collaborations; Communities; Consumption; Crowding; Data; Data Analyses; Development; Disease; Drug Targeting; Drug resistance; Ensure; Epigenetic Process; Etiology; Event; Gene Silencing; Generations; Goals; Institutes; Laboratories; Learning; Libraries; Mass Spectrum Analysis; Mediating; Metadata; Mining; Modality; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Network-based; Neurons; Output; Pathway interactions; Phosphorylation; Proteomics; Psychological reinforcement; Reading; 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; data management; data mining; developmental genetics; drug mechanism; epigenomics; genetic profiling; histone modification; human embryonic stem cell; improved; innovation; metaplastic cell transformation; next generation; novel; novel therapeutic intervention; novel therapeutics; organizational structure; outreach; programs; public health relevance; relating to nervous system; research study; response; small molecule; 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）：该项目的总体目标是检验以下假设：磷酸化介导的信号事件的调节响应扰动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，我们提出了基于质谱（MS）的蛋白质组学测定法，该测定法专门针对> 15,000个扰动条件的细胞中磷酸化性和染色质修饰的定量读数。这些扰动将集中于小分子和基因失活的信号级联和表观遗传标记的调节。我们将研究几种不同的细胞模型系统，包括从人类胚胎干细胞开始的全面研究神经谱系分化。我们建议建立一个中心，以开发必要的基础架构，管道，数据管理和分析，以执行迄今为止将是MS蛋白质组学读取的最大相关实验集。我们还将探索下一代MS Aquisition Technologies，以建立一个可以被公众访问的永久最低的MS数据资源。我们将为基于网络的蜂窝签名（LINCS）程序的库贡献所得的数据和工具，以通过磷酸蛋白质组学和染色质修饰签名与其他数据类型一起通过其他中心为LINC贡献液体的其他数据类型。随之而来的分析将有助于确定新的治疗机会和协同作用，因为磷酸化和表观遗传系统的失调是在越来越多的遗传，发育和环境疾病中鉴定出的最常见的分子病因。 在项目描述的这一组成部分中，我们描述了中心的整体愿景，以广泛的态度绘画我们的科学目标，Logistcal实践，数据分析策略，社区协作计划和行政职能。