Molecular Libraries Probe Production Centers Network

分子文库探针生产中心网络

• 批准号: 8940136
• 负责人: John McKew
• 金额: $ 2238.54万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8940136
• 关键词: Address; Algorithms; Animal Testing; Applications Grants; Area; Asia; Award; Biological; Biological Assay; Biology; Books; Cell Line; Chemicals; Chemistry; Clinical Trials; Collaborations; Computer software; Data; Deposition; Development; Diffuse; Disease; Drug Combinations; Environment; Europe; Ewings sarcoma; Extramural Activities; Foundations; Fruit and Vegetable Extracts; Funding; Genes; Genome; Genomics; Glioma; Goals; Grant; Health; Housing; Human; Human Genome Project; Individual; Informatics; Laboratories; Leadership; Legal patent; Malaria; Malignant Childhood Neoplasm; Manuals; Methods; Molecular Bank; Molecular Target; Names; National Institute of Environmental Health Sciences; National Toxicology Program; Pathway interactions; Peer Review; Pharmaceutical Preparations; Phase; Phenotype; Pontine structure; Pre-Clinical Model; Production; Productivity; Proteins; PubChem; Publications; Publishing; RNA Interference; Rare Diseases; Reporting; Research; Research Personnel; Resources; Robotics; Running; Safety; Schedule; Science; Scientist; Site; Small Interfering RNA; System; Technology; Toxic effect; Toxicology; Translating; Translational Research; United States Environmental Protection Agency; United States National Institutes of Health; Validation; Work; assay development; base; cheminformatics; design; drug discovery; follow-up; high throughput screening; human disease; in vitro Assay; in vivo; insight; interest; member; new technology; novel; novel therapeutics; outreach; outreach program; programs; research study; screening; small molecule; technology development; validation studies

The name of this program changed this year from the NIH Chemical Genomics Center (NCGC) to the Molecular Libraries Probe Production Centers Network (MLPCN) because the MLPCN was transferred from the NIH Common Fund to NCATS. The NCGC activities, which NCATS reported last year, were part of the MLPCN and are included in the MLPCN activities. During the reporting year, the MLPCN worked with over 300 researchers worldwide to advise them on assay design and development, chemistry research, informatics research, technology development projects, and to run high-throughput screens and chemically optimize small molecule leads. In collaboration with the the U.S. Environmental Protection Agency (EPA), the National Toxicology Program (NTP), NIEHS, FDA, NCI, numerous rare disease foundations, and other intramural and extramural laboratories, the MLPCN performed over 31 high-throughput screens on molecular targets and cellular phenotypes important for virtually every area of biology and disease. In order to validate data, we have also deposited 48 hit validation assays and 37 SAR assays in PubChem. The MLPCN also continued its work in the field of siRNA, initiating assay development on 14 projects, completing 18 pilot screens (1,000 genes), and completing 18 primary screens (22,000 genes), and moving into hit validation and follow-up on those projects. 10 new chemical probes of diverse biologies were discovered, and MLPCN scientists published 47 peer reviewed publications during FY14, including 8 high impact publications. The MLPCN filed 3 patent applications during this reporting period. Also during the reporting period, MLPCN deposited a total of 1.28 billion data points into PubChem. MLPCN has deposited 188,906 Substance Identifications and 1,326 Assay Identifications into PubChem. MLPCN continued to apply its chemistry expertise to optimizing probes; a portfolio of 19 in-house chemistry projects and 18 chemistry collaborations was maintained throughout the year. Under leadership from MLPCN, the EPA, and the NTP of NIEHS, Tox21 continued to flourish. Tox21 is an initiative designed to predict the toxicity of chemicals on human health and the environment. This is accomplished by developing in vitro assays for more predictive, mechanistically-based methods than those used with current animal testing. During FY14, Tox21 continued its accelerated production phase. In the current reporting year, MLPCN completed 8 full Tox21 screens and 6 online validation studies. Also, 11 smaller-scale screens, including fruit and vegetable extracts, were analyzed in addition to 17 follow-up experiments on specific, varied cell lines. In FY14, the drug combination program finalized several projects and initiated several new and exciting programs in diverse areas of biology including Malaria, Ewings Sarcoma and the rare pediatric cancer Diffuse Intrinsic Pontine Glioma (DIPG). Novel findings are being examined in advanced preclinical models with high hopes of human clinical trials not far behind. A total of 8 new projects were initiated, 4 of which have come to completion. The support of the NCI Major Opportunities Award and the collaborative strength of many intramural NIH investigators and extramural scientists have made many of these efforts possible. The Assay Guidance manual has continued to evolve and has become a central resource for academic and industrial investigators interested in MLPCN science. With its wide-ranging audience it continues to be a valuable resource that is free and easily accessible. The manual is published as an eBook on the NLM/NCBI site (http://www.ncbi.nlm.nih.gov/books/NBK53196/). In the reporting period, 79,578 unique IP addresses accessed the book. This indicates that a large number of new users are finding the Assay Guidance Manual site useful in early drug discovery and translational science applications. The manual remains a central resource for investigators interested in translational sciences and applying concepts within their own study. Given the MLPCN's continual efficiency improvement program, we were able to increase the throughput of existing robotic screening, informatics, and chemistry systems by improvements in applications, software, and utilization scheduling, driven by both the project teams and Project Management. The MLPCN maintained its existing robotic technology and Bio Safety Levels 1, 2, and 3 facilities during the reporting period. The MLPCN's Outreach program continued its extraordinary record of productivity during the reporting period. MLPCN staff advised 166 outside investigators on assay design and assay development, and with chemistry, informatics, and technology development inquiries. MLPCN scientists gave 50 invited presentations throughout the U.S., Europe, and Asia during the period. MLPCN outreach resulted in the submission of over 68 grant applications for NIH programs. The Assay Guidance manual has continued to evolve and has become a central resource for investigators interested in MLPCN science. During the year, the MLPCN also maintained its status as an active member of the NCI's Chemical Biology Consortium. It currently has two active projects in collaboration with the NCI program, has recently presented one more. NCI has also inquired about the possibility of presenting one further project of interest. Finally, MLPCN's work on its IATAP grants continued.

该计划今年从NIH化学基因组中心(NCGC)更名为分子文库探针生产中心网络(MLPCN)，因为MLPCN从NIH共同基金转移到NCATS。NCATS去年报告的NCGC活动是MLPCN的一部分，并包括在MLPCN活动中。 在本报告年度，MLPCN与世界各地的300多名研究人员合作，就分析设计和开发、化学研究、信息学研究、技术开发项目提供建议，并运行高通量筛选和从化学上优化小分子铅。MLPCN与美国环境保护局(EPA)、国家毒理学计划(NTP)、NIEHS、FDA、NCI、众多罕见疾病基金会以及其他校内外实验室合作，对几乎对生物学和疾病的每个领域都重要的分子靶标和细胞表型进行了31次高通量筛选。为了验证数据，我们还在PubChem中存放了48个HIT验证分析和37个SAR分析。 MLPCN还继续其在siRNA领域的工作，启动了14个项目的化验开发，完成了18个试点筛选(1,000个基因)，并完成了18个初级筛选(22,000个基因)，并进入了HIT验证和这些项目的后续行动。 发现了10种不同生物的新化学探针，MLPCN的科学家在2014财年发表了47篇同行评议的出版物，其中包括8本高影响力的出版物。在本报告所述期间，MLPCN提交了3项专利申请。同样在本报告所述期间，MLPCN向PubChem存入了总计12.8亿个数据点。MLPCN已将188,906个物质标识和1,326个化验标识存入PubChem。MLPCN继续将其化学专业知识应用于优化探针；全年维持了19个内部化学项目和18个化学合作项目的组合。在MLPCN、EPA和NIEHS NTP的领导下，Tox21继续蓬勃发展。Tox21是一项旨在预测化学品对人类健康和环境的毒性的倡议。这是通过开发比目前动物试验使用的更具预测性的、基于机械的方法的体外分析来实现的。在2014财年，Tox21继续其加速生产阶段。在本报告年度，MLPCN完成了8个完整的Tox21筛查和6个在线验证研究。此外，对包括水果和蔬菜提取物在内的11个较小规模的筛查进行了分析，并对特定的、不同的细胞系进行了17个后续实验。在2014财年，药物组合计划敲定了几个项目，并在不同的生物学领域启动了几个新的令人兴奋的计划，包括疟疾、尤文斯肉瘤和罕见的儿童癌症弥漫性固有桥脑胶质瘤(DIPG)。新的发现正在先进的临床前模型中进行检验，对人类临床试验寄予厚望。共启动8个新项目，其中4个项目已竣工。NCI重大机遇奖的支持以及许多NIH内部调查人员和外部科学家的合作力量使这些努力中的许多成为可能。 分析指导手册继续发展，并已成为对MLPCN科学感兴趣的学术和工业调查人员的核心资源。凭借其广泛的受众，它仍然是一个宝贵的资源，是免费的，很容易获得。该手册以电子书的形式在NLm/NCBI网站(http://www.ncbi.nlm.nih.gov/books/NBK53196/).上发布在本报告所述期间，有79,578个独特的IP地址访问了这本书。这表明，大量新用户发现检测指南手册网站在早期药物发现和转化科学应用中很有用。该手册仍然是对翻译科学感兴趣的研究人员的中心资源，并在他们自己的研究中应用概念。 鉴于MLPCN的持续效率改进计划，我们能够通过在项目团队和项目管理的推动下，在应用程序、软件和使用调度方面的改进，增加现有机器人筛选、信息学和化学系统的吞吐量。在本报告所述期间，MLPCN维持了其现有的机器人技术和生物安全一级、二级和三级设施。在本报告所述期间，MLPCN的外联方案继续保持其非凡的生产力记录。MLPCN的工作人员就分析设计和分析开发以及化学、信息学和技术开发方面的问题向166名外部调查人员提供建议。在此期间，MLPCN的科学家们在美国、欧洲和亚洲进行了50次应邀演讲。MLPCN的外联活动导致提交了68多份NIH方案的赠款申请。分析指导手册继续演变，并已成为对MLPCN科学感兴趣的调查人员的中心资源。在这一年中，MLPCN还保持了其作为NCI化学生物学联盟积极成员的地位。它目前有两个与NCI计划合作的活跃项目，最近又提出了一个项目。NCI还询问了是否有可能提出另一个感兴趣的项目。最后，MLPCN关于其IATAP赠款的工作仍在继续。

项目成果

Multiplexing high-content flow (HCF) and quantitative high-throughput screening (qHTS) to identify compounds capable of decreasing cell viability, activating caspase 3/7, expressing annexin V, and changing mitochondrial membrane integrity.

多重高内涵流 (HCF) 和定量高通量筛选 (qHTS) 来鉴定能够降低细胞活力、激活 caspase 3/7、表达膜联蛋白 V 和改变线粒体膜完整性的化合物。

• DOI: 10.1002/9780470559277.ch130060
• 发表时间: 2013
• 期刊: Current protocols in chemical biology
• 作者: Mathews,LesleyA;Keller,JonathanM;McKnight,Crystal;Michael,Sam;Shinn,Paul;Liu,Dongbo;Staudt,LouisM;Thomas,CraigJ;Ferrer,Marc
• 通讯作者: Ferrer,Marc

Identification of thyroid hormone receptor active compounds using a quantitative high-throughput screening platform.

• DOI: 10.2174/2213988501408010036
• 发表时间: 2014
• 期刊: Current chemical genomics and translational medicine
• 作者: Freitas J;Miller N;Mengeling BJ;Xia M;Huang R;Houck K;Rietjens IM;Furlow JD;Murk AJ
• 通讯作者: Murk AJ

A genome-wide siRNA screen to identify modulators of insulin sensitivity and gluconeogenesis.

用于鉴定胰岛素敏感性和糖异生调节剂的全基因组 siRNA 筛选。

• DOI: 10.1371/journal.pone.0036384
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yang,Ruojing;Lacson,RaulG;Castriota,Gino;Zhang,XiaohuaD;Liu,Yaping;Zhao,Wenqing;Einstein,Monica;Camargo,LuizMiguel;Qureshi,Sajjad;Wong,KennyK;Zhang,BeiB;Ferrer,Marc;Berger,JoelP
• 通讯作者: Berger,JoelP

A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.

• DOI: 10.1002/cmdc.201300428
• 发表时间: 2014-03
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Schiller R;Scozzafava G;Tumber A;Wickens JR;Bush JT;Rai G;Lejeune C;Choi H;Yeh TL;Chan MC;Mott BT;McCullagh JS;Maloney DJ;Schofield CJ;Kawamura A
• 通讯作者: Kawamura A

A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice.

• DOI: 10.1210/en.2013-1835
• 发表时间: 2014
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: S. Neumann;Eshel A. Nir;E. Eliseeva;Wenwei Huang;J. Marugan;Jingbo Xiao;Andrés E Dulcey;M. Gershengorn