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以下假设：磷酸化介导的调节 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，我们提议进行质谱（MS）的蛋白质组学测定 该专门针对细胞中磷酸化性信号和染色质修饰的定量读数> 15,000扰动条件。这些扰动将集中于信号级联的调节和 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综合研究神经谱系分化 干细胞。我们建议建立一个中心，以开发必要的基础架构，管道，数据 管理和分析需要执行最大的相关实验集 迄今为止，MS Proteomic读取。我们还将探索下一代MS收购技术 建立一个可永久性的MS数据资源，该资源将被公众访问。我们将做出贡献 由基于网络的蜂窝签名（LINCS）程序库的结果数据和工具 为了通过磷酸蛋白质组学和 染色质修改签名与其他数据类型一致 中心。由此产生的分析将有助于确定新颖的治疗机会和协同作用， 磷酸化和表观遗传系统的失调是两个最常见的分子病因 在越来越多的遗传，发育和环境疾病中鉴定出来。 在项目的这一组成部分中，我们描述了中心在日常运作的物流 从长远来看。我们描述的时间表和里程碑将允许评估我们的中心 随着我们朝着目标迈进，并描述了衡量研究影响的方法。