| ID | Title | Body | Facebook Description | Facebook image | Facebook Title | Facebook Video | Twitter Description | Twitter Image | Twitter Title | Meta tags |
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| 372 | Efficacy & Toxicology | Researchers must demonstrate not only that a new therapeutic candidate is effective against a target disease (i.e., elicits the desired effect) but also that it is safe at the dose intended for human treatment (i.e., does not cause significant toxic side effects). To address efficacy testing, NCATS scientists in the Assay Development and Screening Technologies (ADST) program aim to develop disease-specific models, primarily for rare diseases, against which large libraries of compounds can be screened to identify potential therapeutic candidates. Additionally, through the Tissue Chip for Drug Screening program, the Center supports academic researchers who are developing 3-D human tissue chips that accurately model the structure and function of human organs, such as the lung, liver and heart. Researchers can use these model systems at earlier stages of discovery and development to more efficiently predict whether a candidate agent is safe or toxic in humans. In another area of toxicity testing, NCATS scientists in the collaborative Toxicology in the 21st Century (Tox21) program conduct assay development and toxicity testing for thousands of environmental chemicals to which humans are routinely exposed. | Efficacy & Toxicology | Efficacy & Toxicology | ||||||
| 371 | Molecular Targets | With the many overlapping and redundant molecular pathways in cells, it is crucial to identify and rigorously validate the targets underlying disease progression. NCATS experts develop new methods, approaches, tools and technologies to validate targets in a more efficient and predictable fashion, leading to the creation of safe and effective products. This process greatly increases the likelihood that researchers will be able to develop robust, specific assays to facilitate drug discovery. RNA-based technologies can provide insights into the molecular targets underlying a wide variety of diseases, and these discoveries can lead to the development of novel therapies. Scientists in NCATS’ RNA interference (RNAi) program use gene silencing to better understand gene function. These researchers employ high-throughput RNAi screens to illuminate a range of biological processes, such as which genes that affect the activity of therapeutic agents and novel components of signaling pathways. Investigators from other NIH Institutes and Centers collaborate with NCATS’ RNAi experts to develop assays, conduct genome-wide siRNA screens, and perform rigorous informatics and follow-up. The Extracellular RNA (ExRNA) Communication program, which provides funding to outside researchers on a competitive basis, aims to explore the basic biology of exRNAs to develop better biomarkers, which could improve understanding and diagnosis of many different diseases. | ||||||||
| 369 | Late-Stage Repurposing | If a researcher already has identified a promising approved or existing molecule through initial screening and validation, he or she may need help readying the agent for clinical testing. NCATS experts aid these investigators by supporting the development of regulatory-quality data packages, which enable the drug’s entry into clinical trials for the new disease indication. NCATS provides support for these efforts through its Therapeutics for Rare and Neglected Diseases (TRND) and Bridging Interventional Development Gaps (BrIDGs) programs, which give collaborative partners access to NCATS’ unique resources and drug development expertise. In addition, the Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) program provides funding on a competitive basis to academic researchers who carry out repurposing projects using existing pharmaceutical industry agents. | ||||||||
| 368 | Early-Stage Repurposing | A common first step in repurposing is to screen libraries of already approved compounds — such as the NCATS Pharmaceutical Collection — against a disease-specific biological assay (i.e., one that tests for cell-killing). From such screens, researchers can select a subset of bioactive compounds for further interrogation in secondary and tertiary assays evaluating relevant aspects of disease biology and molecular pathophysiology. NCATS offers various resources to support repurposing efforts across both common and rare diseases. Additionally, the Center’s scientists conduct research in high-throughput assay development and screening, informatics and modeling, and analytical and medicinal chemistry to improve the repurposing process. | ||||||||
| 366 | Probe Development & Lead Optimization | Using high-throughput screening, scientists can employ thousands of small-molecule chemical compounds to test or “probe” the effects of increasing or decreasing the activity of a biological target. This approach works in cell and animal models, making it one of the most powerful tools for target validation (the process of demonstrating that engaging a target provides meaningful therapeutic benefit). Generating these chemical probes requires specialized expertise and facilities, and NCATS has built leading-edge collaborative services to meet those needs. NCATS’ chemical probe development experts collaborate with more than 200 investigators in the government, biopharmaceutical, academic and nonprofit sectors. These partnerships lead to probes used to study a diverse cross-section of human biology, focusing specifically on novel targets and untreatable diseases. Probes enable researchers to investigate protein and cell functions and biological processes, and if appropriate, they can be optimized to become potential drug candidates. This process, called lead optimization, involves refining the chemical structure of a candidate molecule to improve its safety and effectiveness in treating a disease. NCATS’ probe development activities also focus on finding more efficient ways to make probes, using probes to understand diseases and validating targets to treat diseases. The NCATS Approach The Center’s current focus is on developing chemical probes for “non-druggable” targets and pathways. NCATS scientists also work to develop new paradigms for high-throughput screening, informatics and chemistry to make probe development more efficient. Compounds chosen for lead optimization undergo potency, selectivity, solubility and ADME (absorption, distribution, metabolism, and excretion)/pharmacokinetic optimization through the Center’s synthetic chemistry operation. This process narrows candidates to a smaller set of leads that are sufficiently advanced to begin formal preclinical development for a disease of interest. Capabilities Fully automated, large-scale small molecule screening Experience with biochemical as well as cell- and organism-based assay technologies Target-based and phenotypic screening strategies Medicinal chemistry High-throughput parallel synthetic and analytical chemistry Resources Automated robotic screening platform Diverse collections of small molecule libraries that include more than 500,000 approved drugs, natural product extracts, clinical candidates and diversity-focused screening libraries Unique array of biochemical and cell-based readers, including: Luminescence Fluorescence Absorbance FRET TR-FRET FP AlphaScreen High-content imaging Infrastructure for dispensing, dosing and washing assays in formats ranging from 6 to 1,536 wells Instrumentation for a full range of downstream applications to characterize findings in greater detail | ||||||||
| 365 | Assay Development & Screening | One of the first steps in drug development and toxicity testing is creating test systems (assays) on which to evaluate the effects of chemical compounds on cellular, molecular or biochemical processes of interest. Investigators from the biomedical research community submit ideas for assays to NCATS scientists, who help enhance them for high-throughput small molecule screening. The results of these screens, called probes, can help researchers further explore protein and cell functions, biological processes, and effects of environmental chemicals that are relevant to human health and disease. In addition, these probes can become potential therapeutic candidates in the drug development pipeline. NCATS Capabilities NCATS experts develop innovative assay and screening methods to enable a wide range of preclinical activities. Specific capabilities include assay design, optimization, validation and miniaturization; high-content and phenotypic screening; and gene expression analysis. Assay guidance criteria are available below. Quantitative High-Throughput Screening (qHTS) For the Center’s screening purposes, NCATS experts use qHTS, a process in which each compound of a large chemical library is tested at multiple concentrations. Through automated robotic screening, the technology integrates the pharmacologic dose-response relationship with the speed and accuracy of automated HTS. The qHTS method has enhanced the productivity of multiple NCATS activities, and it also has provided the most detailed picture to date of how assay artifacts and library diversity affect interpretation of HTS results. Specific features of the NCATS qHTS platform include: Automated robotic screening 1,536-well format Screening of approximately 40 plates per hour and about 1.5 million compounds per day Pin-tool dispensing Acoustic dispensing Plate incubation and chemical library storage Compounds assayed at 15 concentrations ranging over 4 logs (up to 100 µM) Miniaturization of assay volumes from 2 µL to 6 µL in 1,536-well plate Data processing, curve-fitting and classification through an informatics pipeline Generation of pharmacological actives rather than statistical “hits” (increases reliability and reduces false-positives and -negatives) Matrix Combination Screening Matrix combination screening is an unbiased, high-throughput means to explore hundreds and even thousands of drug-drug pairs for their synergistic, additive and/or antagonistic activities. NCATS scientists use this platform to define potential therapeutic combinations for further testing. Chemical, Pharmaceutical and Natural Product Library Exploration NCATS scientists use qHTS to explore the structure and activity of compounds from the Center’s chemical, pharmaceutical and natural product libraries. The information that emerges from these studies can provide clues to agents’ potential as therapeutics or chemical probes. Chemical Biology Biomedical research functions most efficiently when investigators use chemistry and biology together to address common problems and goals. In service of NCATS’ assay development and screening efforts, chemistry technology projects address fundamental problems and insufficiencies in molecular biology and drug discovery. NCATS supports chemical technologies ranging from novel library design to inventive bioanalytical techniques. Phenotypic Screening and Drug Repurposing Scientists carry out phenotypic screening in early-stage disease research. The results of these efforts inform subsequent target identification and validation studies. High-Throughput Screening Assay Guidance Criteria Criteria Biochemical Cell Based Plate format* 96-well or higher density plate 1,536-well format Assay volume 2-6 μl 96-well or higher density plate 1,536-well format Assay volume 4-6 μl Assay steps = 10 steps with 96-well plate Steps include, reagent additions, timed incubations, plate transfers to incubator, reading, etc. = 10 steps with 96-well plate Steps include, reagent additions, timed incubations, plate transfers to incubator, reading, etc. Minimum time increments and maximum assay duration Minimum assay window is 5 min. (i.e., earliest time point after last reagent addition) < 24 hour is ideal; max is 48 hours Minimum assay window is 5 minutes Reagent addition steps 4 maximum (4 unique reagents max, more if pre-mixed) 4 maximum (4 unique reagents including cells max, more if pre-mixed) Reagent removal steps* No plate coating steps Aspiration steps* Temperature Between RT and 37°C Between RT and 37°C Demonstrated DMSO tolerance* 0.5 - 1% DMSO 0.5 - 1% DMSO Signal: background ratio = 3-fold = 3-fold Day-to-day variation of control (e.g., IC50, EC50) < 3-fold < 3-fold Reagent stability at final working concentration = 8 hours @ RT or on ice bath No online thawing = 8 hours @ RT or on ice bath No online thawing Validation run reagent supply 10 - 96-well plate equivalents 10 - 96-well plate equivalents Protocol Complete detailed protocol All steps, equipment used, all vendor and catalog numbers for reagents Data from 96-well or high-density plate tests Complete detailed protocol All steps, equipment used, all vendor and catalog numbers for reagents Detailed cell culture procedure, passage number Data from 96-well or high-density plate tests Detectors PE ViewLux (Top reading only: FI, TRF, FP, Abs, Luminescence) PE Envision (bottom reading FI, ALPHA) Acumen Explorer (fluorescent laser cytometry) PE ViewLux (Top reading only: FI, TRF, FP, Abs, Luminescence) PE Envision (bottom reading FI, ALPHA) Acumen Explorer (fluorescent laser cytometry) Special For unique reagents, either investigator prepares sufficient quantity for screening or identifies a reliable third-party vendor. Cells must be certified micoplasma-free by direct culture assay and cell-DNA fluorochrome staining. *Table Notes Plate Formats: 96-well plates contain 8 rows x 12 columns with volumes ranging between 50-200 μl; 384-well plates contain 16 rows x 24 columns with volumes ranging between 30-50 μl; 1,536-well plates contain 32 rows by 48 columns with volumes ranging between 2-8 μl. NCATS will convert assays to 1,536-well from 96- or 384-well format. Reagent removal steps: Are any step that requires the removal of material from the well of a microtiter plate. Although such steps may be routine with 96-well plates, they are not recommended on robotic systems using 1,536-well plates. Demonstrated DMSO tolerance: Because all compounds screened are stored in ~100% DMSO and delivered as a 1 to 100 dilution to the assay, the assay sensitivity to between 0.5 percent and 1 percent DMSO must be determined. | ||||||||
| 364 | Target Identification & Validation | Thanks in large part to the Human Genome Project and the dramatic drop in the cost of DNA sequencing, scientists can sort through the roughly 35,000 genes in the human genome to identify sites linked to disease. Discoveries of the molecular basis of diseases point to exciting potential pathways for developing new and better treatments. Most drugs block the action of a particular target protein or cell structure. The only way to be completely certain that a protein is instrumental in a given disease is to test that idea in humans. Obviously, scientists cannot use human clinical trials in the early phases of drug development; therefore, a potential target protein must undergo a validation process. That is, researchers must clearly define the protein’s role in a disease before looking for drugs that act against it or before using it to screen large numbers of compounds for drug activity. Not so long ago, potential drug targets were hard to come by; now the pharmaceutical industry has too many to count. Researchers must sift through vast amounts of data in search of proteins that could be instrumental in human disease — too many potential leads to evaluate one at a time. At NCATS, the goal is to prioritize targets based on how likely they are to lead to a promising therapeutic. The NCATS Approach NCATS supports efforts to develop new methods, approaches, tools and technologies to validate targets in a more efficient and predictable fashion, positioning promising leads at the start of a drug development path that produces safe and effective products. The Center hosts state-of-the-art RNA interference (RNAi) screening capabilities to support target identification and validation. NCATS’ RNAi experts assist investigators from other NIH Institutes and Centers with all stages of project planning and execution, from assay development and genome-wide siRNA screens to informatics, pathway analysis and rigorous follow-up. The facility can produce genome-wide siRNA screens for humans and mice, and microRNA mimic and inhibitor libraries are routinely included. NCATS scientists have in-depth expertise with RNA editing technologies and cell line engineering, and they also perform research to advance the science of RNAi screening technologies. The Center’s assay development capabilities in service of target identification and validation include assay design, optimization, validation and miniaturization. | ||||||||
| 360 | Illuminating the Druggable Genome (IDG) | Results from the Human Genome Project revealed that the human genome contains approximately 20,000 genes. A gene contains (encodes) the information that each cell uses to make (express) a protein, which is essential for the body to function properly. Abnormal protein expression is associated with many human diseases, which makes proteins key targets for therapeutic agents. Approximately 3,000 genes are considered part of the “druggable genome,” a set of genes encoding proteins that scientists can or predict they can modulate using experimental small molecule compounds. Yet the existing clinical pharmacopeia is represented by only a few hundred targets, leaving a huge swath of biology that remains unexploited. Therefore, a large number of proteins remain for scientists to explore as potential therapeutic targets. Much of the druggable genome encodes three key protein families: non-olfactory G-protein-coupled receptors (GPCRs), ion channels and protein kinases. Researchers lack crucial knowledge about the function of many proteins from these families and their roles in health and disease. Better understanding of how these proteins work could shed light on new avenues of investigation for basic science and therapeutic discovery. New Area of Discovery To improve scientific understanding of the three understudied protein families, NIH launched an effort called Illuminating the Druggable Genome (IDG) in 2013, with the first awards made in 2014. The IDG was originally funded as a three-year pilot program sponsored by the NIH Common Fund and designed to create a centralized information repository and develop new technology platforms to study the protein families. Now, the current implementation phase of the IDG Program aims to build on the knowledge and tools developed during the pilot phase and disseminate these IDG-generated resources to the greater scientific community. The NIH IDG working group includes representatives from the National Institute of Mental Health, the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and other Institutes and offices at NIH. By expanding the potential therapeutic space through the IDG program, NIH is clearing a path for more efficient disease-related research and more effective treatments for patients. For more information about IDG, visit the NIH Common Fund website. Researchers supported by the IDG program work with Nature Reviews Drug Discovery to develop new content on a regular basis highlighting understudied protein targets. Learn more about this series and the IDG program or read the collection of articles to find new proteins of interest. Funded Research The current IDG Consortium is made up of the following: The Knowledge Management Center (RFA-RM-16-024), which organizes and shares data and metadata produced by the IDG program, including resources collected during the pilot phase of the program. The scientific community may access these data through Pharos. Data and Resource Generation Centers (RFA-RM-16-026), which use scalable technology platforms to characterize functions of understudied GPCRs, protein kinases and ion channels at the molecular and cellular levels. The Resource Dissemination and Outreach Center (RFA-RM-16-025), which provides the administrative structure for the IDG program, working with all IDG Consortium investigators to collect, curate and disseminate information regarding critical tools and reagents being developed by the IDG Consortium. NCATS plays a crucial role in the IDG program by administering the Resource Dissemination and Outreach Center award and through co-coordination of the overall program with the National Institute of Diabetes and Digestive and Kidney Diseases. View funded awards for the IDG program. | Illuminating the Druggable Genome (IDG) | Illuminating the Druggable Genome (IDG) | ||||||
| 359 | Communities & Research | To ensure community engagement in the research process, research institutions must collaborate with community organizations to identify and understand public health needs. Through the CTSA Program, NCATS supports a broad range of activities that engage communities in health initiatives and clinical research. Working with federal and nonprofit agencies, CTSA Program hubs collaborate with public health professionals, health care providers, researchers and community-based groups to: Develop methods of effective community dialogue and research. Ensure that updated health information is widely available. Provide information and access to clinical trials and studies. Promote participation in clinical trials. Building Community Trust To achieve successful community engagement, partnerships are built on respect and trust. Investigators supported by the CTSA Program value the role of community participation in translating research results into new treatments to improve health, including in underserved communities. Meeting Community Needs CTSA Program investigators conduct their research and outreach efforts through neighborhood service and community centers as well as in mobile units. Projects include education about, prevention of and management of a variety of conditions, including obesity, high blood pressure (hypertension), type 2 diabetes, dental disorders and drug addiction. Community members provide their input on clinical studies and health programs by serving on advisory boards to CTSA Program hubs. Spotlight: Principles of Community Engagement This comprehensive guide, available in English and Spanish, outlines core principles for engaging diverse communities in clinical research activities. Principles of Community Engagement (Second Edition) Principios de Vinculación Comunitaria (PDF - 3,378.12 KB) (Segunda Edición) | ||||||||
| 358 | Scholar and Research Programs | The CTSA Program supports two types of formal clinical research training awards at CTSA Program hubs. Both programs combine formal course work with direct research experience, and many institutions’ programs offer opportunities to pursue additional advanced degrees. All CTSA Program hubs have a KL2 program, which offers formal research training experience to scholars who already have an M.D., Ph.D. or equivalent doctoral degree. Many CTSA Program hubs also include programs that provide predoctoral trainees with an introduction to clinical and translational research through the TL1 program. All students, including those at CTSA Program partner institutions, have access to CTSA Program research facilities, which may include: Training courses, seminars and workshops Use of specialized equipment and databases Access to clinical research mentor expertise Administrative support for research protocols Funding for pilot research projects KL2 Mentored Clinical Research Scholar Awards KL2 awards support mentored research career development for clinical investigators who have recently completed professional training and who are commencing basic, translational and/or clinical research. The CTSA Program hub selects KL2 candidates, providing them with a rich career development experience in a multidisciplinary setting. KL2 appointees — referred to as Clinical Research KL2 Scholars — come from a variety of fields (e.g., medicine, dentistry, nursing, the behavioral sciences, biostatistics and epidemiology) and can receive up to five years of career development support. TL1 Clinical Research Training Awards TL1 awards support students seeking a practical introduction to clinical and translational research. The CTSA Program hub selects TL1 candidates, providing full-time research training support for predoctoral candidates and combined health-professional doctorate-master’s candidates as well as postdoctoral fellows seeking additional training in clinical research. The TL1 goal is to increase the number of well-trained clinician-scientists who can lead the design and oversight of future clinical investigations critical to the overall mission of NCATS and NIH. |
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