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| 392 | Tissue Chip Funding Information | NIH launched the Tissue Chip for Drug Screening program to develop 3-D human tissue chips containing bioengineered models that mimic human physiology. The aim is to use these chips to better predict the safety and effectiveness of candidate drugs. Scientists now are collaborating to combine the chips into an integrated system or human body-on-a-chip. Current Opportunities No funding opportunities are available at this time. Expired Announcements These expired funding announcements include details on the application process, eligibility and timelines for the program: RFA-TR-23-001: Translational Centers for Microphysiological Systems (TraCe MPS) (U2C Clinical Trials Not Allowed) NOT-TR-21-028: Notice of Special Interest (NOSI): Re-issue of Availability of Administrative Supplements for Submission of Tissue Chip Data to the Microphysiology Systems Database (MPS-Db) NOT-TR-20-017: Notice of Special Interest (NOSI) regarding the Availability of Emergency Competitive Revisions to Existing NIH Grants and Cooperative Agreements for Tissue Chips Research on the 2019 Novel Coronavirus NOT-TR-20-016: Notice of Special Interest (NOSI) regarding the Availability of Administrative Supplements for Tissue Chips Research on the 2019 Novel Coronavirus RFA-TR-20-002: Limited Competition: Microphysiological Systems Database Center (MPS DC) (U24 Clinical Trials Not Allowed) PAR-19-138: ImmuneChip: Engineering Microphysiological Immune Tissue Platforms (U01 Clinical Trial Not Allowed) NOT-TR-19-007: Notice of Intent to Publish a Funding Opportunity Announcement for Tissue Chips to Model Nociception, Addiction, and Overdose (UG3/UH3 Clinical Trial Not Allowed) RFA-TR-19-003: HEAL Initiative: Tissue Chips to Model Nociception, Addiction, and Overdose (UG3/UH3 Clinical Trial Not Allowed) RFA-TR-18-006: NextGen Tissue Chip Testing Centers: Validating Microphysiological Systems (U24 Clinical Trial Not Allowed) RFA-TR-18-005: Microphysiological Systems Data Center U24 (Clinical Trial Not Allowed) RFA-TR-18-001: NIH-CASIS Coordinated Microphysiological Systems Program for Translational Research in Space (UG3/UH3 Clinical Trials Not Allowed) NOT-TR-18-014: Notice of Change to Receipt Date on NIH-CASIS Coordinated Microphysiological Systems Program for Translational Research in Space (UG3/UH3 Clinical Trials Not Allowed) (RFA-TR-18-001) RFA-DK-17-035: Microphysiological Systems for Modeling Diabetes (UG3/UH3 - Clinical Trial Not Allowed) RFA-TR-16-017: Microphysiological Systems (MPS) for Disease Modeling and Efficacy Testing (UG3/UH3) NOT-TR-18-027: Notice of Availability of Administrative Supplements for Tissue Chip Consortium Awardees: Development of Tissue Chips to Model Nociception, Opioid Addiction and Overdose RFA-TR-16-019: NIH-CASIS Coordinated Microphysiological Systems Program for Translational Research in Space (UG3/UH3) NOT-TR-18-027: Notice of Availability of Administrative Supplements for Tissue Chip Consortium Awardees: Development of Tissue Chips to Model Nociception, Opioid Addiction and Overdose PA-18-591: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) NOT-TR-19-009: Notice of Correction to Revise Application Due Dates for NOT-TR-19-001 Notice of Availability of Administrative Supplements for Microphysiological Systems Developers: Development of Tissue Chips to Model Nociception, Opioid Addiction and Overdose NOT-TR-18-027: Notice of Availability of Administrative Supplements for Tissue Chip Consortium Awardees: Development of Tissue Chips to Model Nociception, Opioid Addiction and Overdose NOT-TR-19-001: Notice of Availability of Administrative Supplements for Microphysiological Systems Developers : Development of Tissue Chips to Model Nociception, Opioid Addiction and Overdose PA-16-178: Limited Competition: Tissue Chips and Missing Organs (Admin Supp) PA-16-173: Limited Competition: Tissue Chips for Rare Diseases (Admin Supp) RFA-TR-16-006: Tissue Chip Testing Centers: Validating Microphysiological Systems (U24) Tissue Chip Specifications (Excel - 21KB) Confidential Disclosure Agreement (PDF - 27KB) Collaborative Research Agreement (PDF - 110KB) RFA-RM-11-022: Integrated Microphysiological Systems for Drug Efficacy and Toxicity Testing in Human Health and Disease (UH2/UH3) RFA-RM-12-001: Stem/Progenitor Cell-Derived Human Micro-Organs and -Tissues (U18) NCATS acknowledges the following NIH Institutes for their contribution to this trans-NIH program: the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Cancer Institute; the National Eye Institute; the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Biomedical Imaging and Bioengineering; the National Institute of Dental and Craniofacial Research; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Environmental Health Sciences; the National Institute of General Medical Sciences; the National Institute of Neurological Disorders and Stroke; the National Institute of Nursing Research; and the National Institute on Drug Abuse. NIH’s Common Fund and National Institute of Neurological Disorders and Stroke initially led trans-NIH efforts to establish the program. | ||||||||
| 389 | Tissue Chip Frequently Asked Questions | What are tissue chips, and why are they important?Tissue chips are engineered microsystems that represent units of human organs — such as the lung, liver and heart — modeling both structure and function. The chips merge techniques from the computer industry with modern tissue engineering to combine miniature models of living organ tissues on a transparent microchip. Ranging in size from that of a quarter to a house key, the chips are lined by living cells and contain features designed to replicate the complex biological functions of specific organs. Ultimately, this new technology aims to make drug development, especially toxicology and efficacy screening, more reliable, because the tissue chips may provide researchers with insights into predicting more accurately how effective potential drugs would be in humans. This could save money and resources because it would shorten the time it takes for a promising drug candidate to reach clinical trials. How might human tissue chips complement and improve upon existing research models?Approximately 30% of promising medications have failed in human clinical trials because they are determined to be toxic despite encouraging preclinical safety and toxicology studies in animal models. Tissue chips are a newer 3-D human cell-based approach, in contrast to a 2-D approach, that potentially can identify toxic therapeutic candidates in the development process. This may enable scientists to predict more accurately how effective a therapeutic candidate would be in clinical studies. In addition, about 60% of new drugs fail to show effectiveness in treating human diseases due to poor prediction by current in vitro and in vivo models of adverse reactions to candidate compounds during clinical trials. Developing models for human diseases using tissue-on-chip technology may provide better tools for assessing the effectiveness of promising drugs. How will the program and initiatives be evaluated for success?NIH program staff, in coordination with experts from other government agencies and partners, including the IQ Consortium, the Center for the Advancement of Science in Space, pharmaceutical companies and other nonprofits, continue to work in close concert with research investigators to establish milestones and success criteria for these initiatives. For example, at the end of the first five-year program, the aim is to have a set of accurate and reliable cellular and organ microsystems representative of human physiology for the evaluation of drug efficacy and toxicity. These microsystems should be readily available and easily implemented by the broad research community and regulatory agencies.Success measures for future initiatives will depend upon the respective initiative but will include aims such as using chips for disease modeling and efficacy testing and modeling human disease states in microgravity. Milestones and success criteria for these projects will be established with NIH program staff, with insight from the U.S. Food and Drug Administration (FDA) and industry partners. Ultimately, success will be adaptation and use of tissue chip technology across many areas of scientific research. Who will use the tissue chips once they are developed?The data and tools used to create the tissue chips will be published in scientific journals to make these resources available to the broader biomedical research community, in an effort to benefit the public. The initial primary users will be bench scientists from academia, the pharmaceutical industry and regulatory agencies.How will the Tissue Chip for Drug Screening program reduce the time and money needed to develop drugs for patients?A high proportion of drug candidates fail in the development process due to toxicity or lack of efficacy. Often, these toxic effects are not discovered until the drugs are tested in humans. By establishing new predictive models of drug toxicity, we anticipate that tissue chips could reduce the time and money needed to develop drugs by:• Identifying classes of therapeutics that are likely to be effective or fail early in the drug development pipeline. Chips also will allow some tasks in therapeutic development to occur simultaneously, accelerating the process.• Determining which therapeutics can enter into clinical trials. Ultimately, if the devices are successful in predicting efficacy and safety, they could alter the way clinical trials are conducted. These devices likely are transformative, in that they have the potential to change paradigms of how we develop therapies, inform regulatory decision-making processes and shorten clinical trials. What are the roles of the collaborators in this program?The government agencies and partners worked together to develop a collaborative program that builds upon each agency’s knowledge and resources.The Defense Advanced Research Projects Agency (DARPA) is conducting a separate but parallel program. DARPA is funding two grants, one to the Wyss Institute at Harvard University and the other to the Massachusetts Institute of Technology, both of which also are NIH tissue chip grant recipients, to develop engineering platforms capable of integrating 10 or more organ systems.The FDA is exploring how this new technology might be used to assess drug safety prior to approval for first-in-human studies.The IQ Consortium also has partnered with NCATS to contribute industry expertise to the Tissue Chip Consortium and help with the efforts to validate the technology, leading to future efforts for making the technology more widely available to the community. How much money is NIH contributing to this effort?NIH has committed up to $75 million over five years to date to its Tissue Chip for Drug Screening program. In fiscal year 2017, NIH awarded more than $20 million.How does this initiative support the NCATS mission?The Tissue Chip for Drug Screening program supports the mission of NCATS by fostering the development of innovative methods and technologies needed to accelerate the pace at which we develop new treatments for patients, demonstrate the usefulness of these technologies and disseminate that information to the broader research community.What effect would the tissue chips have on drug development efforts in the pharmaceutical and biotechnology sector?Improved drug safety testing is needed across the entire spectrum of drug development to accelerate the availability of new treatments for patients. Tissue chips would benefit basic and clinical researchers throughout the entire pharmaceutical and biotechnology sector.Will the tissue chip devices be made available commercially?The intellectual property developed under these grants will be covered under the Bayh-Dole Act. The NIH-funded grantee will determine how to further develop and commercialize any tissue chips resulting from the research conducted. Companies that have been formed to commercialize tissue chip technology include Emulate, CNBio and Nortis. | ||||||||
| 385 | About Tissue Chip | A lot of promising medications have failed to be safe and effective in human clinical trials despite promising preclinical studies. We are addressing this problem through the Tissue Chip for Drug Screening program. We coordinate with other NIH Institutes and Centers and the U.S. Food and Drug Administration (FDA). This lung-on-a-chip serves as an accurate model of human lungs to test for drug safety and efficacy. (Wyss Institute for Biologically Inspired Engineering, Harvard University Photo) Tissue chips are built from human cells. Also called organs-on-chips, they mimic the structure and function of our heart, kidneys, lungs and other organ systems. Scientists are developing and using tissue chips to test the potential effects of drugs on those tissues in a faster and more effective way than current methods. Learn more about these projects. With flexible funding from the Cures Acceleration Network, we focus on developing high-need cures and reducing major barriers between research discovery and clinical trials. Our Tissue Chip for Drug Screening program aims to speed the translation of basic discoveries into the clinic. By creating an integrated human body-on-a-chip, researchers will be able to test the possible effects of a drug or other substance across the entire body before testing in people. Because they use human cells, tissue chips are also useful research tools to study human diseases and conditions when animal models do not mirror the pathology or are unavailable. They support NIH’s position that non-animal model approaches can reduce the need for animals in research but will require further improvement to completely replace them. Learn more about all of the Tissue Chip for Drug Screening program initiatives. Program History 2010 The NIH Common Fund announced a new collaboration with the FDA to advance regulatory science. In the fall of 2010, NIH and the FDA announced awards as part of the Regulatory Science program. One of those awards included a project to develop a heart-lung tissue chip model to test the safety and efficacy of drugs. 2011 Recognizing the potential to advance tissue chip technology, NIH, the FDA and the Defense Advanced Research Projects Agency held a joint workshop that led to a coordinated effort between the agencies. 2012 NCATS’ launch of the Tissue Chip for Drug Screening program in 2012 resulted in the development of 3-D tissue chips designed to represent a number of human organ systems. NIH awarded 12 projects that supported the development of 3-D cellular microsystems that represent human organ systems and seven projects that explored the use of stem and progenitor cells to differentiate into multiple cell types that represent the cellular architecture within organ systems. 2014 In 2014, researchers began working together on linking individual organs on chips to develop a human multi-organ model system, incorporating several chips that accurately represent various human organs and tissues and capturing interactions between different organs. The human model system is being designed to replicate the complex human response to compound exposure and is intended to predict the safety of potential drugs in a faster, more cost-effective way than current methods. By combining all major organ systems to form a human-body-on-a-chip, NCATS ultimately intends to accelerate the translation of these basic discoveries into the clinic. 2016 NCATS announced a partnership and new funding opportunity with the Center for the Advancement of Science in Space (CASIS) in October 2016. The Tissue Chips in Space initiative will enable NCATS and CASIS to collaborate and coordinate efforts that will help refine tissue- and organ-on-chip platforms for in-flight experiments at the International Space Station U.S. National Laboratory ((ISS National Lab), so that scientists can better understand diseases and translate their findings to affect human health on Earth. On Oct. 13, 2016, NCATS announced awards for several Tissue Chip Testing Centers that provide a way for independent testing and validation of platforms developed by Tissue Chip for Drug Screening program-supported scientists, ensure the availability of tissue chip technology and promote the adoption of this technology by the broader research community, particularly among regulatory agencies and pharmaceutical companies. In October 2016, NCATS announced a new funding opportunity through its Tissue Chips for Disease Modeling and Efficacy Testing initiative that will support further development of tissue chip models of human disease that mimic the pathology in major human organs and tissues. The goals of this new initiative are to (1) support studies to develop in vitro disease models using primary tissue or induced pluripotent stem cell (iPSC)-derived patient cell sources on tissue-/organ-on-chip platforms, (2) determine the disease relevance of these models by preliminary testing of key experimental features and (3) test the effectiveness of candidate drugs. 2017 In June 2017, NCATS issued five two-year awards for a total of up to approximately $6 million in response to a funding opportunity to use tissue chip technology for translational research on board the ISS National Lab for the benefit of human health on Earth. During the first phase of the Tissue Chips in Space initiative, researchers will develop and test tissue chips on the ISS National Lab in a microgravity environment. In the second phase, they will further demonstrate the functional use of the tissue chip models for more defined experiments on the ISS National Lab. In September 2017, NCATS announced 13 awards to develop 3-D tissue chip research platforms that model disease and test drug efficacy prior to clinical trials. (In February 2018, NCATS issued an additional award.) Through the Tissue Chips for Disease Modeling and Efficacy Testing initiative, the Tissue Chip awardees will study a wide range of common and rare diseases, from rheumatoid arthritis, kidney disease and human influenza A viral infection to amyotrophic lateral sclerosis, hereditary hemorrhagic telangiectasia and arrhythmogenic cardiomyopathy. In the second phase of the awards, researchers will partner with pharmaceutical companies to further evaluate the usefulness of validated disease models — those that accurately mimic disease biology — in assessing the effectiveness of candidate drugs. In December 2017, NCATS, CASIS and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) announced a new funding opportunity for tissue- and organ-on-chip research at the ISS National Lab to study human physiology and disease. Data from this research — which will feature tissue chips (or organs-on-chips) — will help scientists develop and advance novel technologies to improve human health. Learn more about Tissue Chip program partnerships and how the program works. 2018 In July 2018, NCATS announced the availability of administrative supplements for Tissue Chip Consortium awardees to develop tissue chip models for pain, opioid addiction and overdose. In September 2018, NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases issued three five-year awards for tissue chip systems that model type 2 diabetes. In addition, NCATS renewed funding for two Tissue Chip Testing Centers and a database center. In October 2018, NCATS, NIBIB and ISS National Lab announced four new Tissue Chips in Space awards designed to study tissue- and organs-on-chips that mimic major organs and systems in the human body in the extreme environment of space at the ISS National Lab. Scientists will use this information to assess biomarkers, bioavailability, efficacy and toxicity of therapeutic agents prior to clinical trials. In December 2018, NCATS announced the launch of the first NIH-supported tissue chips into space for research. 2019 In 2019, NCATS, with support from the Helping to End Addition Long-term℠ Initiative (NIH HEAL Initiative℠), awarded grants to five research teams in support of their work developing and testing tissue chips to better understand the biological mechanisms and behaviors underlying addiction and opioid use disorders. The research projects include the development of tissue chips for evaluating nociception, addiction or overdose, as well as testing the developed tissue chips’ functionality in these areas 2020 In the spring of 2020, NCATS administered — through the “Clinical Trials” on a Chip program — 10 grants supporting the development of microphysiological, bioengineered models of human tissues and organ systems to inform clinical trial design and execution. These models will guide work for both common and rare diseases, which will improve the success rate of new therapeutics in drug development. In the summer of 2020, supplementary support was rapidly distributed to tissue chip investigators who shifted their research focus to urgent COVID-19 work. With support from the Coronavirus Aid, Relief, and Economic Security (CARES) Act, COVID-19 Tissue Chip Supplement awards were granted to 12 research teams that used their tissue chip research to evaluate the properties of SARS-CoV-2, COVID-19 disease pathology, and varying drugs and therapeutics for use against COVID-19 infection. 2021 In 2021, the Tissue Chip Testing Center (TCTC) project periods closed. In order to continue the valuable research from these centers, which began in 2016, the TCTC teams worked to become financially independent and self-sustaining, establishing companies and consortiums to extend their research beyond the project periods. Contact Danilo Tagle, Ph.D. | ||||||||
| 381 | Automation | The automation experts at NCATS are responsible for the maintenance, operation and continuous improvement of a full range of laboratory instrumentation and processes. These automation engineers and machinists support NCATS activities in high-throughput screening and assay development and optimization. Resources Systems supported by the automation team include: Primary Screening System With three robotic arms for plate transportation, a storage capacity of more than 3 million compound wells (approximately 2,000 1,536-well compound plates), more than 1.5 million assay wells (approximately 1,100 1,536-well assay plates), and an ability to run multiple assays in parallel, NCATS can achieve world-class screening productivity while maintaining the high level of data quality required by researchers. Center experts have developed custom software to monitor and control the system, in addition to archiving the complete process history for every screen in real time. Secondary Screening System With two robotic arms for plate transportation and a storage capacity of nearly 1 million compound or assay wells (about 600 1,536-well compound or assay plates), NCATS experts use this system to screen smaller scale compound libraries not present on the primary screening system. This platform is designed to complement the primary system, and it is easily customizable, allowing for the rapid integration of additional screening technologies. Tox21 Screening System This system contains a single robotic arm for plate transportation and a storage capacity of about 1.5 million compound wells (about 1,000 1,536-well compound plates) and more than 1.5 million assay wells (approximately 1,100 1,536-well assay plates). With a pin tool and two acoustic dispensers for compound addition, four low-volume dispensers for reagent addition, and three plate readers enabling a variety of assay detection methods, this system can rapidly screen, in triplicate, the Toxicology in the 21st Century (Tox21) library of 10,000 compounds. NCATS experts monitor and control this system with the same custom software used for the primary screening system. RNAi Screening System This high-throughput system has two robotic arms for plate transportation with incubators for assay plate storage and plate stackers to facilitate continuous system operation. A multichannel pipettor, low volume dispensers, an aspirator for plate washing and two different plate readers support a wide variety of detection methods for this RNAi-focused system. Experts Sam Michael Carleen Klumpp-Thomas | ||||||||
| 379 | Tox21 in Action | The Toxicology in the 21st Century (Tox21) program is a federal collaboration among NCATS and the National Toxicology Program at the National Institute of Environmental Health Sciences; the U.S. Environmental Protection Agency; and the Food and Drug Administration. Tox21 researchers aim to develop better toxicity assessment methods to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to negative health effects. Read the latest news about this program.March 2019NCATS Assay Recognized in Top Ten List of Innovative Scientific AchievementsNCATS developed a screening test to identify molecules that block the process of growing new blood vessels. With the test, NCATS scientists found both known and potential new anticancer drugs. The work earned a spot on the Society for Laboratory Automation and Screening’s top 10 innovative scientific achievements list for 2018.October 2018NCATS Scientists Prioritize Compounds to Advance Research on Mitochondrial DamageNCATS scientists collaborated with other federal agencies to develop an approach that enables researchers to prioritize environmental chemicals according to their ability to disrupt mitochondrial activity.March 2018Tox21 Collaborators Release New Strategic Plan for Chemical TestingOn March 8, 2018, Tox21 program partners from NCATS, the National Toxicology Program at the National Institute of Environmental Health Sciences, the Environmental Protection Agency, and the Food and Drug Administration published a new strategic and operational plan to broaden the scope of their research activities to address new challenges. The collaborators are launching new cross-partner research projects to address five new areas of focus. The three-year projects each have support from a minimum of two Tox21 partners and will be reviewed annually by Tox21 leadership. | /sites/default/files/tox21_1260x630.jpg | Tox21 in Action | /sites/default/files/tox21_1260x630.jpg | Tox21 in Action | ||||
| 378 | Analytical Chemistry | We support research primarily focused on small molecule analysis and purification. Our state-of-the-art laboratory has a wide variety of instrumentation for medicinal, synthetic and analytical chemistry to support early-stage chemical development.CapabilitiesSemi-Preparative PurificationThe analytical chemistry team routinely purifies samples with material in the range of milligrams to grams. Major and minor components (<0.1 percent) have been isolated for additional testing and characterization. The team’s automated processing involves dispensing samples into 1D barcoded vials, Matrix™ 2D barcoded tubes and/or 96-well plates for efficient tracking, storing and testing. The entire process from receiving the sample to final plating takes less than one week. Sample AnalysisLiquid chromatographyThe group uses a variety of liquid chromatographs to determine identity and purity. It uses single quadrupole liquid chromatography/mass spectrometry instrumentation for high-throughput automated analysis. All data are stored on the team’s network and can be accessed through its proprietary SMART software. Due to the wide variety of analytes tested, the team’s range of analytical detectors includes ultraviolet (UV), mass spectrometry (MS; positive and negative mode), evaporative light scattering detector and fluorescence. The experts achieve formula confirmation and identity determination of unknowns using time-of-flight mass spectrometry (TOF/MS).Chiral chromatography for analysis and purificationMethods development with the chiral chromatography screening protocol includes analysis on seven different chiral stationary phases. Use of several mobile phase conditions enables development of the best chiral separation. The group routinely determines chemical purity and enantiomeric purity. The use of an inline chiral detector facilitates the determination of relative optical rotation. Matching the stationary phase of analytical columns with the corresponding stationary phase in both semi-preparative and preparative columns enables purification of milligram to gram quantities of the sample. The isolated enantiomers are returned as powders after chiral chromatography analysis to ensure purity of the material.Nuclear Magnetic Resonance (NMR) AnalysisNMR spectroscopy is arguably the most powerful analytical tool a chemist can use to identify and confirm organic molecules. Medicinal chemists at NCATS have access to two Varian 400 MHz VNMRS instruments equipped with autosamplers every day. Furthermore, the team routinely conducts advanced 1D (NOE, APT, DEPT) and 2D (COSY, NOESY, HSQC, HMBC) experiments for structural analysis and validation. Each instrument currently uses a 5-millimeter PFG AutoX dual broadband probe outfitted with a ProTune module allowing for NMR spectra of high-band (1H, 19F) and low-band (13C, 15N, 31P) nuclei. An XR401 sample cooler attached to the probe enables variable temperature experiments ranging from −40°C to 105°C. By using microsample tubes, the team can get spectral data with minimal material.Resources· Agilent 1100 HPLC Systems· Agilent 1200 Series High-Throughput LC/UV/MS System· Agilent 6210 TOF/MS· Biotage SP Purification Systems· Chiral Chromatography Screening LC System· Gilson GX-281 Prep LC System· PDR-Chiral Advanced Laser Polarimeter· PerkinElmer 341 Polarimeter· PerkinElmer Spectrum 100 FT-IR· Sirius Automation MultiTasker Robotics System· Teledyne ISCO CombiFlash System Sq16x· Varian 400 MHz Nuclear Magnetic Resonance· Waters ACQUITY UPLC System· Waters FractionLynx Prep LC System ContactChris LeClair, Ph.D. | ||||||||
| 377 | Tox21 Operational Model | Tox21’s federal partners include the U.S. Environmental Protection Agency (EPA), the U.S. Food and Drug Administration (FDA) and NIH, with leadership from NCATS and the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences. These agencies work together to advance in vitro toxicological testing.Partner RolesNTP and the National Center for Computational Toxicology in the EPA Office of Research and Development co-fund Tox21. Each partner brings key expertise, including:• Animal toxicology (NTP)• Computational toxicology (EPA)• Human toxicity data (FDA)• In vitro cell-based assays, quantitative high-throughput screening and informatics (NCATS)The ultimate goal for EPA and the FDA is to apply the knowledge gained from Tox21 research to the products these agencies regulate. Phase IThe completed first phase of Tox21 involved testing 2,800 compounds in more than 50 assays using the high-throughput robotic screening system now at NCATS. The resulting data are available in public databases, such as the National Library of Medicine’s PubChem, EPA’s ToxCast and NTP’s Chemical Effects in Biological Systems.Phase IIThe second phase of Tox21 involves testing a collection of more than 10,000 compounds (Tox21 10K library). The initial focus was on creating assays to test the compounds’ effects on nuclear receptors (AR, AhR, ERα/β, FXR, GR, LXR, PPARδ, PPARγ, PR, PXR, RXR, TRβ,VDR, RORγ, CAR and ERR); stress response pathways (p53, NF-κB, pH2AX, endoplasmic reticulum stress, mitochondrial membrane potential, ARE/Nrf-2, heat shock response, DNA damage, and real-time cytotoxicity and viability); developmental pathways (retinol signaling, Hedgehog/Gli and SBE/Smad); G-protein-coupled receptor signaling (TRHR and TSHR); and others (HDAC and AChE).Consortium partners continue to develop a range of secondary and tertiary follow-up assays to further define and characterize activities identified in the initial high-throughput screens. All testing results are made publicly available through NIH and EPA chemical toxicity databases. In addition, NCATS created a free Tox21 data browser that gives researchers additional information about the chemicals.Phase IIITox21 leaders have begun to focus on developing a third phase for the program, as described in the new strategic and operational plan. This phase will involve:• Using more physiologically relevant cells (i.e., primary, stem cells and high-content imaging technologies) in screening assays• Increasing the number of molecular pathways tested by measuring gene expression• Expanding the compound library to include new drugs approved for clinical use in recent years• Incorporating high-throughput gene expression profiling, including concentration-response modeling• Studying non-mammalian model organisms, including zebrafish and Caenorhabditis elegans• Using Tox21 datasets to build models that predict specific compounds’ effects on human health and using the power of crowdsourcing to enlist the help of the larger scientific community to create these models• Accommodating new strategic direction through the formation of cross-partner projectsAssay ProposalsAlthough Tox21 experts optimize internally developed assays and screening methodologies, they also accept and evaluate assay proposals submitted by outside investigators, both within and outside the government. Learn more about submitting an assay. ContactAnna Rossoshek | /sites/default/files/tox21_1260x630.jpg | Tox21 Operational Model | /sites/default/files/tox21_1260x630.jpg | Tox21 Operational Model | ||||
| 376 | Informatics (old) | Broadly, the goal of informatics is to transform raw numeric data obtained from large-scale experiments into actionable decisions in chemistry and biology. Given the wide range of science carried out at NCATS, the Center’s informatics team applies techniques from a broad array of disciplines, including cheminformatics, bioinformatics, computational biology and chemistry, to enable experimental decision making. Key to these activities is the development of algorithms and software to disseminate research results to the broader community. NCATS’ informatics scientists also form collaborative relationships with other investigators to develop robust assay designs and analytics. Additionally, they develop chemical libraries, such as the NCATS Pharmaceutical Collection and a broader collection of drug-like compounds. NCATS’ informatics activities are focused into two areas. The first involves day-to-day support of data analysis for early discovery research projects. The second area consists of research and development of novel analysis methodologies of translational research data and studying the process of how scientists translate novel discoveries into new medicines. Capabilities General informatics capabilities include: Cheminformatics and computational chemistry Bioinformatics and genetic analysis Mathematical and statistical modeling Scientific software development NCATS experts tackle a wide variety of translational research tasks. The informatics team collaborates closely with experimentalists to develop robust assay designs and analytics. They perform ligand- and protein structure-related modeling tasks, ranging from quantitative structure-activity relationship modeling to docking and molecular dynamics simulations. The team also supports bioinformatics analyses to probe pathophysiology, develop new response biomarkers and analyze sequencing data. In addition to scientific tasks, the informatics team develops software for a variety of scientific applications, including compound registration, scientific data management, and high-throughput screening operations. The team also supports the back-end databases and services on which many tools and applications depend. Informatics and Quantitative High-Throughput Screening (qHTS) NCATS’ qHTS technology directly depends on the informatics team’s computational infrastructure to convert measured responses from millions of microtiter plate wells to dose-response curves, enabling the identification of active and inactive compounds. Given that a screen can generate results for more than 400,000 compounds, the informatics team has developed an efficient grid-based curve-fitting algorithm that has been shown to outperform R and Excel in model fitting tests. A stand-alone version of the code also is available. Currently, NCATS’ back-end databases host upwards of 60 million dose-response curves. Resources Software and tools include: NCATS Pharmaceutical Collection (NPC) Browser Provides access to NPC compounds, offering searching and exporting capabilities. NCATS Chemical Genomics Center CurveFit A public, open-source version of the informatics team’s curve-fitting software, which automatically fits and classifies thousands of dose-response curves. NCATS Predictor Offers the scientific community a tool for virtual screening of drug-like compounds to find desirable biological profiles and help optimize investigational compounds. Global Ingredient Archival System (ginas) A registration system that makes it easier for regulators and other stakeholders to exchange information about the ingredients in medicinal products. Pharos A user interface to the Knowledge Management Center for the Illuminating the Druggable Genome (IDG) program. Biomedical Data Translator Organizing comprehensive access to biomedical research data, including objective signs and symptoms of disease, drug effects, and intervening types of biological data relevant to understanding pathophysiology. NCATS Inxight: Drugs Online portal that aggregates reliable, curated drug development data from multiple existing sources, all in one place. Experts Dammika Nandanie Amugoda, M.S. Lu Chen, Ph.D. Xin Hu, Ph.D. Ruili Huang, Ph.D. Danny Katzel Claire Malley, M.S. Ewy A. Mathé, Ph.D. (Director) Tyler Peryea Timothy Sheils Min Shen, Ph.D. Noel Southall, Ph.D. Hongmao Sun, Ph.D. Greg Tawa, Ph.D. Gergely Zahoránszky-Kőhalmi, Ph.D. Alexey V. Zakharov, Ph.D. Tongan Zhao | ||||||||
| 375 | Tox21 Program Goals | The goal of Tox21 is to develop more efficient and less time-consuming approaches to predict how chemicals may affect human health. Initially, the main focus of Tox21 was to help prioritize chemicals for more extensive testing using traditional methods. However, Tox21’s ultimate aim is to develop strategies for agencies to use in regulating chemicals and reducing the current reliance on animal testing for toxicological evaluations.To achieve these goals, the objectives of the Tox21 program are to:• Identify environmental chemicals that lead to biological responses and determine their mechanisms of action on biological systems• Prioritize specific compounds for more extensive toxicological evaluation• Develop models that predict chemicals’ negative health effects in humans, including diseases• Annotate all human biochemical pathways and design assays (tests) that can measure these pathways’ responses to chemicalsTo address evolving challenges in toxicology more broadly, the Tox21 partners developed a new strategic and operational plan that expands the focus of the program’s research activities. These new areas of focus are:1. Develop alternative test systems that predict human toxicity and dose response2. Address key technical limitations of current in vitro test systems3. Curate and characterize long-lasting in vivo toxicity studies4. Set scientific confidence in in vitro test systems and combined assay series5. Refine and launch in vitro methods for characterizing pharmacokinetics and in vitro dispositionsTo assist in the new strategic direction and the expansion in focus of the Tox21 partnership, a central functional group called the cross-partner project was created. Cross-partner projects are defined research activities that fall into one of the five areas of focus and must have project support from two or more Tox21 partners. The projects have three-year terms and are reviewed annually by the Tox21 leadership, allowing a more formal research planning and execution process.Tox21 Scientific ThemesWithin Tox21, the current screening effort includes two themes:1. Generating fit-for-purpose cellular models for primary and secondary screeningTox21 experts are developing a range of hepatocyte (liver), neuron, endothelial (vascular), keratinocytes (skin) and cardiomyocyte (heart) cell models — including “disease-in-a-dish” models, 3-D culture methods and multicellular co-culture models, most derived from inducible pluripotent stem cells — to further characterize hits from primary screening of 10,000 compounds (Tox21 10K library).2. Developing high-throughput gene expression capabilitiesTox21 scientists have developed high-throughput gene expression capabilities, including RNAseq and single-cell RNAseq, to serve both Tox21 partners and NCATS projects. The data analysis team has implemented a pipeline to allow data processing and statistical and systems analyses, which includes concentration-response point-of-departure determination and pathway analysis using BioPlanet. | /sites/default/files/tox21_1260x630.jpg | Tox21 Program Goals | /sites/default/files/tox21_1260x630.jpg | Tox21 Program Goals | ||||
| 373 | About Tox21 | Throughout their lives, people are exposed to thousands of chemicals in food, household cleaning products, medicines and the environment. However, scientists know little about the potential of most of these substances being toxic to human health. About Tox21The Toxicology in the 21st Century (Tox21) program is a federal collaboration among NIH’s NCATS and the National Toxicology Program at the National Institute of Environmental Health Sciences; the Environmental Protection Agency; and the Food and Drug Administration. Tox21 researchers aim to develop better toxicity assessment methods to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to negative health effects. Learn more about the goals of the Tox21 program.Using the center’s high-throughput robotic screening system, NCATS scientists are testing a collection of 10,000 environmental chemicals and approved drugs (called the Tox21 10K library) for their potential to disrupt biological pathways that may result in toxicity. The team prioritizes promising compounds identified from primary screening for further in-depth investigation. Learn more about how the Tox21 program works.Tox21 HistorySince Tox21 began in 2008, the collaborative research team has developed and validated in vitro cell-based assays (tests) using quantitative high-throughput screening. The researchers have identified, developed, optimized and screened more than 100 assays.The Tox21 program includes three research phases, structured with guidance from two reports — Toxicology in the 21st Century: The Role of the National Toxicology Program and The U.S. Federal Tox21 Program: A Strategic and Operational Plan for Continued Leadership.Our TeamPopulate the Our Team module using this page: https://ncats.nih.gov/tox21/capabilities/team | Toxicology in the 21st Century (Tox21) program researchers develop methods to test whether certain chemical compounds will disrupt processes in the human body that may lead to negative health effects. | /sites/default/files/Tox21_Robot_900x850px.jpg | About Tox21 | Toxicology in the 21st Century (Tox21) program researchers develop methods to test whether certain chemical compounds will disrupt processes in the human body that may lead to negative health effects. | /sites/default/files/Tox21_Robot_900x850px.jpg | About Tox21 |
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