Administration

行政

• 批准号: 8932069
• 负责人: Jacob David Jaffe
• 金额: $ 4.74万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932069
• 关键词: Back; Biological Assay; Biological Models; Cancer Etiology; Cell model; Cells; Collaborations; Communication; Communities; Complex; Decision Making; Disease; Documentation; Drug Targeting; Electronics; Elements; Ensure; Environment; Epigenetic Process; Etiology; Evaluation; Event; Feedback; Funding; Gene Silencing; Goals; Grant; Guidelines; Head; Institutes; Instruction; Journals; Laboratories; Learning; Libraries; Logistics; Mass Spectrum Analysis; Measures; Mediating; Metadata; Methods; Mining; Molecular; Monitor; Network-based; Neurons; Phosphorylation; Production; Progress Reports; Proteomics; Psychological reinforcement; Publications; Reading; Reagent; Research; Research Infrastructure; Research Personnel; Resource Sharing; Resources; Schedule; Services; Signal Transduction; Structure; System; Techniques; Technology; Testing; TimeLine; United States National Institutes of Health; base; chromatin modification; collaborative environment; computer infrastructure; conflict resolution; developmental genetics; experience; human embryonic stem cell; meetings; next generation; novel therapeutics; organizational structure; outreach; programs; research study; response; small molecule; success; tool

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 we describe the logistics of how our center will operate on a day-to-day basis and over the long term. We describe timelines and milestones that will allow evaluation of our center as we progress towards our goals, and describe methods to measure the impact of our research.

该项目的总体目标是检验磷酸化介导的调节的假设 响应扰动的信号事件可以通过改变其表观遗传来建立新的细胞状态 风景。为了实现这一目标，我们建议进行基于质谱 (MS) 的蛋白质组分析 专门针对 > 细胞中磷酸信号传导和染色质修饰的定量读数 15,000 个扰动条件。这些扰动将集中在信号级联的调制和 小分子和基因失活的表观遗传标记。我们将研究几种不同的细胞模型 系统，包括从人类胚胎开始的神经元谱系分化的综合研究 干细胞。我们建议建立一个中心，以开发必要的基础设施、管道、数据 执行最大一组相关实验所需的管理和分析 迄今为止的 MS 蛋白质组读数。我们还将探索下一代 MS 采集技术 建立可供公众访问的永久可开采的 MS 数据资源。我们将做出贡献 将生成的数据和工具提供给基于集成网络的蜂窝签名库 (LINCS) 程序 目的是通过磷酸化蛋白质组学和方法在不同的扰动之间建立联系 染色质修饰签名与其他数据类型一起贡献给 LINCS 中心。由此产生的分析将有助于确定新的治疗机会和协同作用，如 磷酸信号传导和表观遗传系统的失调是两种最常见的分子病因 在越来越多的遗传、发育和环境疾病中被发现。 在该项目的这一部分中，我们描述了我们中心日常运作的后勤工作 基础和长期。我们描述了时间表和里程碑，以便对我们的中心进行评估 当我们朝着目标前进时，并描述衡量我们研究影响的方法。