Pharmaco Response Signatures and Disease Mechanism

药物反应特征和疾病机制

• 批准号: 9098801
• 负责人: PETER Karl SORGER
• 金额: $ 214.52万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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/9098801
• 关键词: Accounting; Antibodies; Apoptosis; Award; Biochemical; Biological Assay; Cell Cycle Arrest; Cell Extracts; Cell Line; Cell surface; Cells; Clinical; Clinical Investigator; Collaborations; Collection; Communities; Complex; Computational algorithm; Computing Methodologies; Data; Data Analyses; Data Collection; Data Set; Databases; Development; Disease; Dose; Drug Interactions; Education and Outreach; Ensure; Extracellular Matrix; Fuzzy Logic; Generations; Goals; Gray unit of radiation dose; Growth; Health; Human; Image; Image Analysis; Immune; Immune response; Immunoassay; Immunofluorescence Immunologic; Knowledge; Learning; Life; Linear Regressions; Machine Learning; Mass Spectrum Analysis; Measurement; Measures; Messenger RNA; Methods; Modeling; Molecular; Online Systems; Pathway Analysis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Phosphotransferases; Polypharmacy; Population; Post-Translational Protein Processing; Principal Component Analysis; Production; Proteins; Proteome; Proteomics; Research; Research Personnel; Sentinel; Signal Transduction; Signaling Protein; Statistical Methods; Statistical Models; Stem cells; Technology; Testing; Tumor Cell Line; Work; analytical method; base; cell fixing; cell type; cellular imaging; cytokine; data visualization; drug discovery; epigenome; forest; genome browser; genomic data; improved; induced pluripotent stem cell; innovation; kinase inhibitor; learning strategy; live cell imaging; member; network models; novel; novel strategies; operation; outreach; phenotypic data; predicting response; programs; research study; response; senescence; small molecule; tool; usability; web services; web site

DESCRIPTION (provided by applicant): The overall goal of the HMS LINCS Center is to delineate the fundamental principles of cellular response to perturbagens at the level of single-cells and cell populations and to make response data routinely available via web-based browse, query and programmatic interfaces. This will involve the development and testing of new measurement methods, computational algorithms, and response signatures for diverse human cell types exposed to perturbations individually and in combination. We will emphasize the systematic collection of data not currently available in existing public databases including live and fixed-cell imaging, biochemical data on signaling proteins and multi-factorial drug-response phenotypes. A focus on diverse transformed and primary cells, including those derived from healthy and diseased donors, and on clinical grade small molecules (kinase inhibitors and epigenome drugs) will increase the translational impact of our work. The proposed LINCS Center represents a continuation of a program in operation for ~3.5 years under a LINCS pilot phase U54 award. We will expand the scope and sophistication of our Center, devoting significant effort to (i) improving the quality of data analysis and visualization, particularly wih respect to the complexities of perturbagen polypharmacy (ii) accelerating the release of perturbagen-response signatures using methods that have been demonstrated to yield reliable and informative data, with a particular emphasis on primary and non-transformed cells (iii) developing and applying new measurement methods, particularly mass spectrometry for analysis of cell populations and live-cell imaging for analysis of single cells. The work will involve nine complementary but independent aims. In Data Generation, Aim 1 will perform systematic analysis of perturbagen responses at a single-cell level. Aim 2 will collect multiplex protein and mRNA data on perturbagen response using a set of complementary imaging, mass spectrometry and bead-based assays. Aim 3 will apply LINCS methods to non-transformed immune cells and induced pluripotent stem cells, and explore if signatures can guide a detailed medicinal chemistry campaign. In Data Analysis, Aim 4 will construct perturbagen-response signatures using statistical modeling, network inference and machine learning methods. Aim 5 will develop new approaches to understanding and analyzing drug interactions on multiple phenotypes in single cells. Aim 6 will develop a novel compressed sensing framework for analyzing the poly-pharmacology of kinase inhibitors. Aim 7 will enhance the query, browse and explore functions of the HMS LINCS website and database and its integration with the UCSC Genome Browser. In Community Interaction and Outreach, Aim 8 will implement diverse training and outreach activities, including collaboration with LINCS and non-LINCS research groups. In Administration, Aim 9 will ensure effective management of the Center, sustained access to tools and data produced within the LINCS Project, and compliance with program goals.

描述(由申请人提供)：HMS Lincs中心的总体目标是在单细胞和细胞群体水平上描述细胞对扰动的反应的基本原理，并通过基于网络的浏览、查询和编程界面提供常规的反应数据。这将涉及开发和测试新的测量方法、计算算法和对单独和组合暴露于扰动下的不同人类细胞类型的响应特征。我们将强调对现有公共数据库中目前无法获得的数据的系统收集，包括活细胞和固定细胞成像、信号蛋白的生化数据和多因素药物反应表型。关注不同的转化细胞和原代细胞，包括来自健康和疾病捐赠者的细胞，以及临床级小分子(激酶抑制剂和表观基因组药物)将增加我们工作的翻译影响。拟建的Lincs中心代表着Lincs试点阶段U54合同下运营约3.5年的计划的延续。我们将扩大我们中心的范围和复杂性，致力于(I)提高数据分析和可视化的质量，特别是关于微扰多药的复杂性；(Ii)使用已被证明能够产生可靠和信息丰富的数据的方法，加快微扰反应特征的发布，特别是对原代和未转化细胞的研究；(Iii)开发和应用新的测量方法，特别是用于细胞群体分析的质谱学和用于单细胞分析的活细胞成像。这项工作将涉及九个相辅相成但独立的目标。在数据生成中，AIM 1将在单细胞水平上对微扰反应进行系统分析。AIM 2将使用一套互补成像、质谱分析和基于珠子的分析来收集关于扰动反应的多重蛋白质和mRNA数据。Aim 3将把Lincs方法应用于未转化的免疫细胞和诱导的多能干细胞，并探索签名是否可以指导详细的药物化学活动。在数据分析中，AIM 4将使用统计建模、网络推理和机器学习方法构建扰动响应特征。AIM 5将开发新的方法来理解和分析药物与单细胞中多种表型的相互作用。AIM 6将开发一种新的压缩传感框架，用于分析激酶抑制剂的多种药理作用。AIM 7将增强HMS Lincs网站和数据库的查询、浏览和浏览功能，并增强其与UCSC基因组浏览器的集成。在社区互动和外联方面，AIM 8将开展各种培训和外联活动，包括与Lincs和非Lincs研究小组合作。在管理方面，AIM 9将确保对中心的有效管理，持续访问Lincs项目中产生的工具和数据，并遵守计划目标。