Pharmaco Response Signatures and Disease Mechanism

药物反应特征和疾病机制

• 批准号: 8787853
• 负责人: PETER Karl SORGER
• 金额: $ 214.55万
• 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/8787853
• 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; Genome; Genomics; Goals; Gray unit of radiation dose; Growth Factor; Human; Image; Image Analysis; Imagery; Immune; Immune response; Immunoassay; Immunofluorescence Immunologic; Knowledge; Learning; Life; Linear Regressions; Machine Learning; Mass Spectrum Analysis; Measurement; Measures; Messenger RNA; Methods; Metric; 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; drug discovery; epigenome; forest; improved; induced pluripotent stem cell; innovation; kinase inhibitor; member; network models; novel; novel strategies; operation; outreach; programs; public health relevance; 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水平上描述细胞对扰动因素作出反应的基本原理，并通过基于网络的浏览、查询和编程接口定期提供反应数据。这将涉及开发和测试新的测量方法、计算算法以及单独或组合受到扰动的不同人类细胞类型的响应特征。我们将强调现有公共数据库中目前未提供的数据的系统收集，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。关注多样化的转化细胞和原代细胞，包括来自健康和患病供体的细胞，以及临床级小分子（激酶抑制剂和表观基因组药物）将增加我们工作的转化影响。拟建的 LINCS 中心是 LINCS 试点阶段 U54 项目的延续，该项目已运行约 3.5 年。我们将扩大中心的范围和复杂程度，投入大量精力：（i）提高数据分析和可视化的质量，特别是考虑到扰动剂多药学的复杂性（ii）使用已被证明可以产生可靠和信息丰富的数据的方法加速释放扰动剂反应特征，特别强调原代细胞和非转化细胞（iii）开发和应用新的 测量方法，特别是用于分析细胞群的质谱法和用于分析单细胞的活细胞成像。 这项工作将涉及九个互补但独立的目标。在数据生成中，目标 1 将在单细胞水平上对扰动因子反应进行系统分析。目标 2 将使用一组互补成像、质谱和基于微珠的检测收集有关扰动原反应的多重蛋白质和 mRNA 数据。目标 3 将 LINCS 方法应用于未转化的免疫细胞和诱导多能干细胞，并探索特征是否可以指导详细的药物化学活动。在数据分析中，目标 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。目标 5 将开发新方法来理解和分析单细胞中多种表型的药物相互作用。 Aim 6 将开发一种新颖的压缩传感框架，用于分析激酶抑制剂的多药理学。 Aim 7将增强HMS LINCS网站和数据库的查询、浏览和探索功能以及与UCSC基因组浏览器的集成。在社区互动和外展方面，目标 8 将实施多样化的培训和外展活动，包括与 LINCS 和非 LINCS 研究小组的合作。在管理方面，目标 9 将确保中心的有效管理、持续访问 LINCS 项目内生成的工具和数据以及遵守计划目标。