DAta | National Center for Advancing Translational Sciences

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18177	NCATS Team’s Rapid Test Finds Promising Therapies for Myositis	NCATS scientists have developed an approach to rapidly test thousands of existing drugs to identify promising therapies for myositis, a rare autoimmune disease. Results from hundreds of drug tests on human muscle cells (in background) reveal two potential candidates (in foreground) to treat the disease. (NCATS and NHGRI; created by Darryl Leja, NHGRI)October 22, 2020Idiopathic inflammatory myopathy, also known as myositis, is a rare muscle disease with no effective therapies and few experimental treatments in development. But a new research initiative by NCATS scientists could point to promising new options. They swiftly tested thousands of existing drugs to find therapeutics that may target a key trigger in myositis.Myositis is an autoimmune disease characterized by chronic inflammation of the muscles. A person’s own immune system attacks their muscle cells, leading to skeletal muscle weakness and pain, as well as complications in the skin, lungs and circulatory system. Myositis affects an estimated 2,000 to 4,000 people in the United States, and incidence of the disease is on the rise.“There is no specifically approved therapy for myositis, and there is no cure,” explained Travis B. Kinder, Ph.D., a postdoctoral research fellow at NCATS and the study’s corresponding author. “Our goal was to find new therapeutics for this rare condition.”Current treatments include anti-inflammatory steroids, as well as drugs that suppress the immune system and biologic agents that modulate the immune system. However, first-line options, such as high-dose prednisone, can have serious side effects — particularly for children with myositis — and current therapies do not stop muscle inflammation completely or return muscles to normal.With funding from the Cure Juvenile Myositis Foundation, Kinder and his fellow study investigators, NCATS senior research scientist Patricia K. Dranchak, Ph.D., and NCATS principal investigator James Inglese, Ph.D., developed an approach to rapidly test thousands of existing drugs and identify candidates for further study. Their findings appeared online May 27 in ACS Chemical Biology.The first step was to identify a promising therapeutic target. The NCATS researchers picked a target that may contribute to the immune system’s attack on muscle cells: the inflammatory pathway between type I interferon (IFN) and major histocompatibility complex (MHC) class I. IFN modulates the immune system’s response to infection, and MHC class I attracts the immune system to attack pathogens and diseased cells.In the weakened skeletal muscles of myositis, growing evidence links high levels of type I IFN and the overproduction of MHC class I. That duo typically springs into action when a virus attacks. However, scientists have yet to find evidence of a viral trigger in myositis, which means IFN and production of MHC class I could be therapeutic targets in myositis.Using CRISPR/Cas9 genome editing, the research team developed a line of human muscle cells to test the IFN–MHC class I pathway. They then began the hunt for drugs to stop the cycle of inflammation and autoimmunity in myositis, turning to NCATS’ library of thousands of investigational and U.S. Food and Drug Administration (FDA)-approved drug compounds.The researchers analyzed the compounds in that library through a process known as quantitative high-throughput screening (qHTS), which can test thousands of compounds and drugs at the same time. Using qHTS, they rapidly tested 4,679 unique compounds at assorted concentrations to assess their pharmacological effects on the targeted inflammatory pathway. Of the thousands of drugs tested, NCATS scientists focused on 12 drugs and compounds that showed the most promise.The most effective drug proved to be the antibiotic echinomycin, which had been developed and abandoned as a potential cancer therapy. Drugs that inhibit cellular signaling proteins called kinases were the largest class of promising compounds screened. Three FDA-approved Janus kinase inhibitors were nearly 100% effective at inhibiting the targeted pathway: ruxolitinib, baricitinib and tofacitinib. Of the three, ruxolitinib was most potent.Several compounds that interfere with gene activity also actively blocked the targeted pathway. Those compounds include FDA-approved panobinostat, vorinostat and doxorubicin. Another promising investigational drug, givinostat, is already in trials for Duchenne muscular dystrophy, a rare disease that also features muscle inflammation.The Duchenne therapeutic connection highlights how drugs that target the type I IFN–MHC class I pathway could have an impact beyond myositis, Kinder explained. Other autoimmune diseases that might benefit from such treatments include rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus and systemic sclerosis.One of the next research steps would be animal-model myositis trials, particularly for some of the less-studied drugs, Kinder added. He and his colleagues plan to continue screening new Janus kinase inhibitors and novel compounds, explore potential environmental triggers for myositis, and search the genome to discover new target genes and pathways for novel therapeutic interventions.	NCATS team developed an approach to rapidly test thousands of existing drugs to identify promising therapies for myositis.	/sites/default/files/Myositis_900x600px_0.jpg	NCATS Team’s Rapid Test Finds Promising Therapies for Myositis	NCATS team developed an approach to rapidly test thousands of existing drugs to identify promising therapies for myositis.	/sites/default/files/Myositis_900x600px_1.jpg	NCATS Team’s Rapid Test Finds Promising Therapies for Myositis
18078	NIH Begins Large Clinical Trial to Test Immune Modulators for Treatment of COVID-19	UPDATE: View the June 2022 release to see preliminary results of the ACTIV-1 Immune Modulators trial. Read the preprints for abatacept and infliximab.Illustration of a cytokine storm response to infection with the new coronavirus SARS-CoV-2. A cytokine storm is a severe immune reaction that results in greatly elevated levels of inflammatory immune proteins (cytokines, purple) in the body. (Fernando Da Cunha/Science Photo Library)October 16, 2020 The National Institutes of Health has launched an adaptive Phase 3 clinical trial to evaluate the safety and efficacy of three immune modulator drugs in hospitalized adults with COVID-19. Some COVID-19 patients experience an immune response in which the immune system unleashes excessive amounts of proteins that trigger inflammation — called a “cytokine storm” — that can lead to acute respiratory distress syndrome, multiple organ failure and other life-threatening complications. The clinical trial aims to determine if modulating that immune response can reduce the need for ventilators and shorten hospital stays. The trial, known as ACTIV-1 Immune Modulators (IM), will determine if the therapeutics are able to restore balance to an overactive immune system.Part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, the trial expects to enroll approximately 2,100 hospitalized adults with moderate to severe COVID-19 at medical facilities in the United States and Latin America. The National Center for Advancing Translational Sciences (NCATS), part of NIH, will coordinate and oversee the trial with funding support from the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, in support of the Trump administration’s Operation Warp Speed goals. BARDA’s Clinical Studies Network will be responsible for operationalizing the trial through a task order awarded to contract research organization Technical Resources International, Inc.“This is the fifth master protocol to be launched under the ACTIV partnership in an unprecedented timeframe, and focuses efforts on therapies that hold the greatest promise for treating COVID-19,” said NIH Director Francis S. Collins, M.D., Ph.D. “Immune modulators provide another treatment modality in the ACTIV therapeutic toolkit to help manage the complex, multi-system conditions that can be caused by this very serious disease.”ACTIV-1 IM is a randomized placebo-controlled trial that uses an adaptive master protocol. One of the hallmarks of master protocols is that they allow coordinated and efficient evaluation of multiple investigational agents as they become available. This enables maximum flexibility to swiftly weed out drugs that do not demonstrate effectiveness, identify those that do in a short time frame, and rapidly incorporate additional experimental agents into the trial.The ACTIV public-private partnership selected three agents for the study from a pool of over 130 immune modulators initially reviewed based on several factors including their relevance to COVID-19, strong evidence for use against inflammatory reaction and cytokine storm and availability for large-scale clinical studies. The initial agents are infliximab (REMICADE), developed by Janssen Research & Development, LLC., one of the Janssen Pharmaceutical Companies of Johnson & Johnson; abatacept (ORENCIA), developed by Bristol Myers Squibb; and Cenicriviroc (CVC), an investigational late-stage agent developed by AbbVie.All participants in the trial will receive remdesivir, which is the current standard of care treatment of hospitalized patients with COVID-19. Convalescent plasma and dexamethasone will be allowed at the discretion of the site investigator and in accordance with national guidelines. They will be randomly assigned to receive a placebo or one of the immune modulators as an add-on treatment. The trial will study the different combination treatment regimens with respect to illness severity, recovery speed, mortality and hospital resource utilization. Enrollment is now open, and the trial is expected to last approximately six months. Results will be available shortly after the trial is completed, or possibly sooner if analysis conducted during the trial indicates that one or more of the drugs is beneficial. To ensure that the trial is being conducted in a safe and effective manner, an independent data and safety monitoring board will oversee the trial and conduct periodic reviews of the accumulating data.The protocol team chair is William G. Powderly, M.D., director of the Institute for Clinical and Translational Sciences and co-director of the Division of Infectious Diseases at Washington University School of Medicine in St. Louis. NCATS’ Clinical and Translational Science Awards (CTSA) Program and the Trial Innovation Network will play a key role in adding U.S. study sites and enrolling patients, including those from communities disproportionately affected by COVID-19.“The CTSA Program’s nimbleness and innovation in conducting clinical trials — along with the network’s extensive capacity and broad geographical reach — have positioned it to rapidly implement this important trial,” said NCATS Director Christopher P. Austin, M.D. “The innovative trial design will allow efficient evaluation of three different potential COVID-19 treatments concurrently, delivering new possible treatments for patients more quickly and valuable insights into the science of clinical translation.”NIH announced the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative in April 2020 to develop a national research response to prioritize and speed the development of the most promising COVID-19 treatments and vaccines. Coordinated by the Foundation for the National Institutes of Health, ACTIV brings together partners from government, industry, academia and non-profit organizations. Visit the ACTIV Therapeutics page.Media Contact: NCATS Information Officer, ncatsinfo@mail.nih.govAbout the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov.About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov.About HHS, ASPR, and BARDA: HHS works to enhance and protect the health and well-being of all Americans, providing for effective health and human services and fostering advances in medicine, public health, and social services. The mission of ASPR is to save lives and protect Americans from 21st century health security threats. Within ASPR, BARDA invests in the innovation, advanced research and development, acquisition, and manufacturing of medical countermeasures — vaccines, drugs, therapeutics, diagnostic tools, and non-pharmaceutical products needed to combat health security threats. To date, 55 BARDA-supported products have achieved FDA approval, licensure or clearance. For more on BARDA’s development portfolios and on partnering with BARDA, visit medicalcountermeasures.gov. To learn more about federal public health and medical preparedness and response, visit phe.gov.NIH…Turning Discovery Into Health®	NIH launched a large clinical trial to evaluate three immune modulator drugs in hospitalized adults with COVID-19.	/sites/default/files/C0492806-Covid-19_cytokine_storm_illustration_BLUE_900x600_0.jpg	Clinical trial to test immune modulators for treatment of COVID-19	NIH launched a large clinical trial to evaluate three immune modulator drugs in hospitalized adults with COVID-19.	/sites/default/files/C0492806-Covid-19_cytokine_storm_illustration_BLUE_900x600_1.jpg	Clinical trial to test immune modulators for treatment of COVID-19
18099	About the NCATS Education Branch	The NCATS Education Branch provides national leadership to foster development of the field of translational science. To accomplish this, the Branch engaged in a range of activities as depicted in the figure below. Intramurally, through the Division of Preclinical Innovation, the Education Branch creates novel and holistic training opportunities for a diverse pool of early-career scientists to gain translational science skills through engagement in hands-on research, seminars, career talks and journal clubs. Education Branch Publications and Events Publications Advancing Translational Science Education — This article highlights new approaches for translational science education that aim to capitalize on decades of translational science advances and expand and diversify the translational science workforce. It shares an initial set of Translational Science Principles, developed by NCATS from case studies of highly successful translational science initiatives, which characterize effective approaches to accelerate progress along the translational pipeline. These principles are one approach to facilitate dissemination of experiential knowledge in translational science and engage broader audiences in translational science education and training. Teaching Principles of Translational Science to a Broad Scientific Audience Using a Case Study Approach: A Pilot Course from the National Center for Advancing Translational Sciences — This article describes the pedagogical rationale, design and implementation of a case-study based course in translational science. It offers strategies and lessons learned for developing educational opportunities in translational science for participants across training and career stages and professions. Evaluation of an Online Case Study-Based Course in Translational Science for a Broad Scientific Audience: Impacts on Students' Knowledge, Attitudes, Planned Scientific Activities, and Career Goals — This article shares evaluation methods and findings for an online case study-based course in translational science for a general scientific audience. It also reflects on needed directions in the evaluation of translational science education and training opportunities. Supplementary materials include the complete evaluation instruments. The National Center for Advancing Translational Sciences’ Intramural Training Program and Fellow Career Outcomes — This article describes how the NCATS training program equips young scientists with translational science skills that lead to early research successes and prepares them for a broad range of science-based careers. Past Events Translational Science Education Roundtable March 10-11, 2022 1:00-4:00 p.m. EDT Agenda and Participation List (PDF - 185KB) Presentation: Joni L Rutter, Ph.D. (PDF - 4.2MB) Presentation: Jessica Faupel-Badger, Ph.D., MPH (PDF - 2.3MB) Roundtable Summary (PDF - 258KB) Members of the NCATS Education Branch Acting Branch Chief: Amanda L. Vogel, Ph.D., M.P.H. Director of Intramural Translational Training: Belen Hurle, Ph.D. Lead for Intramural Trainee Development: Marcus G. Hodges, Ph.D. AAAS Science and Technology Policy Fellow: Emily J. Davis, Ph.D. Contact the Education Branch at NCATSDPITrainEd@mail.nih.gov	Fostering the development of the field of translational science.		About the NCATS Education Branch	Fostering the development of the field of translational science.		About the NCATS Education Branch
18090	The Emerging Field of Translational Science	Translational research is the scientific process by which observations in the laboratory, clinic and community are turned into interventions that improve the health of individuals and the public — from diagnostics and therapeutics to medical procedures and behavioral changes. Translation is a multidisciplinary, iterative process involving basic research, preclinical research, clinical research, clinical implementation, public health, and patient involvement. Learn more about the translational science spectrum. As shown in the Drug Discovery, Development and Deployment Maps, the multidisciplinary nature of translational research requires sophisticated interactions among scientific collaborators across a range of expertise. Such interactions create scientific and operational complexities that produce both opportunities and challenges for the research. For example, they might accelerate innovation, but they also may create such challenges as poor communication and coordination of workflows. Translational science is the emerging field of investigation focused on building the evidence base for effective scientific and operational approaches in translational research. This evidence, when applied to new or ongoing research initiatives, can enhance innovativeness, effectiveness and efficiency, addressing core challenges in the biomedical research enterprise. Read more about the promise of translational science to advance biomedical research in the articles “Translating Translation” and “Opportunities and Challenges in Translational Science.” Leadership in Translational Science NCATS provides national and international leadership to advance the field of translational science, through both its extramural and intramural activities. Extramurally, NCATS supports advances in translational science via the Clinical and Translational Science Award (CTSA) Program. Intramurally, the NCATS Division of Preclinical Innovation (DPI) develops and implements novel approaches for translational science training. The NCATS Education Branch provides leadership to advance the field of translational science, with a focus on training, education and career pathways. Using Translational Science to Address Challenges in Translational Research NCATS is working toward the development of effective scientific and operational approaches to address common challenges in translational research. Learn more about the issues in translation NCATS aims to address: Predictive efficacy and toxicology De-risking therapeutic development Clinical research efficiency Collaboration and partnerships Data transparency and release Download the Transforming Translational Science fact sheet to learn more about translational science.	Understanding the principles underlying the translational process.		The Emerging Field of Translational Science	Understanding the principles underlying the translational process.		The Emerging Field of Translational Science
18123	Data Transfer Agreement Signatories	The institutions listed below have executed a Data Transfer Agreement (DTA) (PDF - 139KB) with NCATS. The N3C Long COVID Tenant does not yet include data from all of the institutions listed. Data is made available after harmonization.Learn more about the process:Data transfer (PDF - 139KB)Data acquisitionData ingestion and harmonizationInstitutions not on the list but interested in contributing data to the N3C Long COVID Tenant should review the related forms and resources or email us. DTA SignatoriesAdvocate Health Care NetworkThe Alliance at the University of Puerto Rico, Medical Sciences CampusArkansas Children’s Research InstituteAurora Health Care Inc.Baylor College of MedicineBoard of Regents of the University of Oklahoma Health Sciences CenterBoston Medical CenterBrown UniversityCarilion Medical CenterCharleston Area Medical Center (CAMC)Children’s Hospital ColoradoChildren's Hospital of PhiladelphiaChildren’s National HospitalCincinnati Children’s Hospital Medical Center (CCHMC)Columbia University Irving Medical CenterDuke University, acting for and on behalf of its School of MedicineEmory UniversityGeorge Washington University Hospital (GWU)Honor HealthIcahn School of Medicine at Mount SinaiJohns Hopkins University on behalf of its School of MedicineLeland Stanford Jr. UniversityLouisiana Public Health InstituteLoyola University of ChicagoLoyola University Medical CenterMaine Medical Center Research InstituteMary Hitchcock Memorial Hospital & Dartmouth Hitchcock ClinicMass General Brigham IncorporatedMayo Clinic, RochesterMedical College of WisconsinMedical University of South Carolina (MUSC)MedStar Health Research InstituteThe MetroHealth SystemThe MITRE CorporationMontana State UniversityMontefiore-Einstein Center for Health Data InnovationsThe Nemours FoundationNorthShore University HealthSystemNorthwestern UniversityNYU Grossman School of Medicine, an administrative unit of New York UniversityOCHIN, Inc.Ochsner Clinic FoundationOhio State UniversityOregon Health & Science University (OHSU)The Pennsylvania State UniversityThe Queens Medical CenterRegenstrief Institute Inc.Research Foundation for SUNY obo University of BuffaloRockefellerRush University Medical CenterRutgers Biomedical/Health Sciences RBHSSanford ResearchScripps Research InstituteStony Brook UniversityTufts UniversityUniversity Hospitals Cleveland Medical CenterUniversity Hospitals of ClevelandUniversity Medical Center Management Corporation d/b/a University Medical Center New OrleansUniversity Medical Center of Southern NevadaUniversity of Alabama Birmingham (UAB)University of Arkansas acting for and on behalf of the University of Arkansas for Medical SciencesUniversity of California DavisUniversity of California IrvineUniversity of California Los AngelesUniversity of California San DiegoUniversity of California San Fran (USF)University of ChicagoUniversity of CincinnatiUniversity of Colorado School of MedicineUniversity of FloridaUniversity of IowaUniversity of Kansas Medical CenterUniversity of KentuckyUniversity of Massachusetts Med School WorchesterUniversity of MiamiUniversity of MichiganUniversity of MinnesotaUniversity of Mississippi Medical CenterUniversity of Nebraska, Board of RegentsUniversity of New Mexico Health Sciences CenterThe University of North Carolina Health Care SystemUniversity of North TexasUniversity of RochesterUniversity of Southern CaliforniaUniversity of Texas Health San AntonioUniversity of Texas Health Sciences Center at HoustonUniversity of Texas Medical Branch at Galveston, d/b/a UTMB Health (UTMB)University of UtahThe University of VermontUniversity of Virginia (UVA)University of WashingtonUniversity of Wisconsin - MadisonUniversity of Illinois ChicagoVanderbilt University Medical CenterVirginia Commonwealth UniversityWake Forest Health SciencesThe Washington UniversityWeill Medical College of Cornell UniversityWest Virginia University Research CorporationYale University	List of institutions that have executed a Data Transfer Agreement with NCATS to contribute data to the N3C Data Enclave.		Data Transfer Agreement Signatories	List of institutions that have executed a Data Transfer Agreement with NCATS to contribute data to the N3C Data Enclave.		Data Transfer Agreement Signatories
18048	NCATS Translational Science Training Program Sets Young Scientists on Paths to Career Success	Working directly with NCATS researchers, young scientists in the Division of Preclinical Innovation’s fellows program learn translational science fundamentals such as team-based collaboration and multidisciplinary research skills. (Daniel Soñé Photography)October 13, 2020An NCATS training program that equips young scientists with translational science skills leads to early research successes and prepares them for a broad range of science-based careers at the benchtop and beyond.Those are the key findings from a review of fellows who completed the training program directed by NCATS’ Division of Preclinical Innovation (DPI). Researchers assessed the productivity and career outcomes of 213 fellows who completed their DPI training program from December 2011 through August 2019. The study appeared in CBE: Life Sciences Education.“Many of our fellows are pursuing a variety of science-related career paths, including those in industry and government, as well as into academia,” said Brittany M. Haynes, Ph.D., a scientific program specialist at NCATS and corresponding author of the study. “We believe the in-depth translational science training and professional development at DPI prepare them to enter many career sectors and job functions.”DPI immerses the fellows in translational science, teaching them the scientific and operational principles behind the process of turning research observations into medical interventions. Through a curriculum of research training, education and professional development, the fellows learn such translational science fundamentals as team-based collaboration and multidisciplinary research skills. They work directly with DPI scientists on research projects, learn to communicate and collaborate across scientific disciplines, and build individual career development plans.“Our fellows have the opportunity to contribute to a wide array of research projects, and there’s so much expertise under one roof at DPI,” stated Jessica Faupel-Badger, Ph.D., M.P.H., Education Branch chief at NCATS. “There’s a cycle of collaboration between our groups in which fellows play an integral role. This type of collaborative opportunity for an early-career scientist is another aspect that makes the DPI training environment truly unique.”Training program participants include short-term high school, undergraduate and graduate fellows, as well as those in longer-term postbaccalaureate and postdoctoral positions. Postbaccalaureate fellows spent an average of 1.5 years in the training program, whereas postdoctoral fellows averaged 2.5 years.Nearly half of the training alumni (51%) were summer fellows during their DPI training, and nearly one in five alumni (19%) were in a postdoctoral position during their DPI fellowship. The remaining 30% were in postbaccalaureate or predoctoral fellowships. Approximately four in 10 alumni were female (41%).Among the fellows’ research achievements during their time at DPI —Sixty-six percent of postbaccalaureate, 63% of pre- and postdoctoral, and 8% of summer alumni published their research while in the program. In addition, it is likely the fellows had more manuscripts in preparation or under review when they completed the program, Faupel-Badger noted.The fellows contributed to 235 publications. That number likely underestimates their productivity because it includes only the DPI fellows’ research published during their training at DPI and not post-training.The DPI fellows contributed to 11 patent applications and 11 inventions.The patents and inventions, in particular, demonstrate how the DPI fellows rapidly learn to translate their research observations into real-world interventions. “These are biomedical scientists who learn to communicate their research findings to people in nonscience professions and have a direct impact on public health,” Haynes explained. “Those successes are a testament to our fellows becoming boundary crossers.”Once the DPI training ends, the fellows’ translational science skills make them competitive candidates for multiple opportunities in the science workplace. “By learning all the steps involved in translational science, fellows develop a broader sense of what career options are available to them,” Haynes explained.Among fellows’ career destinations after their DPI training —Seventy-one percent of alumni who have finished their education are in science-focused careers or research positions.Sixty-three percent of postbaccalaureate alumni who are continuing their education in academia are pursuing either a Ph.D. or an M.D.-Ph.D., whereas 23% are pursuing an M.D.Forty-three percent of the postdoctoral fellows now work for a government agency, 24% work at for-profit companies, 21% work in academia, and 10% work with nonprofit organizations.The DPI training program continues to expand, rising to 57 fellows as of Aug. 1, 2020. That total includes 21 postbaccalaureate fellows, six predoctoral fellows and 30 postdoctoral fellows. The DPI now plans to develop surveys for its fellows before and after training, as well as for its alumni. The findings should sharpen the understanding of how DPI’s translational science training shapes fellows’ career choices, helping DPI refine its curriculum to develop translational scientists.To learn more about translational science training opportunities, visit the NCATS Translational Science Education & Training site. For personal perspectives on the DPI fellowship initiative, learn how the training program set one summer fellow on the path to a science career, watch a postbaccalaureate fellow share her experiences in the program, and find out why one DPI postdoctoral fellow decided to become a translational sciences researcher.	NCATS training program helped prepare young scientists for early research successes and science-based careers.		NCATS Training Program Sets New Scientists on Paths to Career Success	NCATS training program helped prepare young scientists for early research successes and science-based careers.		NCATS Training Program Sets New Scientists on Paths to Career Success
18042	Translational Science Interagency Fellowship Projects and Mentors	h5 {margin-bottom:.5rem;font-size:20px;} h6 {color:#00626F;} Fellows in the Translational Science Interagency Fellowship (TSIF) program will be matched with an NCATS/U.S. Food and Drug Administration (FDA) mentor pair to work on a specific project. Below is the list of projects and mentors for the current application cycle.TSIF Projects and MentorsCombining Machine Learning and In Vitro Genotoxicity Assays for Assessing Potential Carcinogenicity and Mutagenicity of Nitrosamine Impurities in Drug ProductsFDA Mentor NamesHuixiao Hong, Ph.D.Ru ChenPosition and Organizational AffiliationHuixiao Hong: SBRBPAS Expert / Branch Chief, Division of Bioinformatics and Biostatistics, NCTRRu Chen: Staff Fellow, Office of Translational Sciences, CDERContact Information (email/telephone)Huixiao.Hong@fda.hhs.gov / 870-543-7296Ru.Chen@fda.hhs.gov/240-402-0302NCATS Mentor NamesMenghang Xia, Ph.D.Ruili Huang, Ph.D.Position and Organizational AffiliationMenghang Xia: Tox21 Biology Team Lead, DPIRuili Huang: Tox21 Informatics Team Lead, DPIContact Information (email/telephone)mxia@mail.nih.gov /301-827-5359huangru@mail.nih.gov /301-827-0944Research Project SummaryMany nitrosamines have been found to be carcinogenic and mutagenic and have been identified as impurities existing in drug products, casting doubt on the safety of these products. The FDA has published a guidance for industry on the control of nitrosamine impurities in clinical used drugs for preparing initial risk assessments. Thus, assessing the potential carcinogenicity and mutagenicity of nitrosamines is vital for facilitating safety evaluation of drug products in regulatory science. Evaluation of numerous nitrosamines using animals for their carcinogenicity and mutagenicity is not feasible. Therefore, alternative methods such as in vitro assays and machine learning for assessing the potential carcinogenicity and mutagenicity of nitrosamines are urgently needed to assist safety evaluation of drug products. This proposal will use machine learning combined with in vitro genotoxicity assays to assess the potential carcinogenicity and mutagenicity of nitrosamines present in drug products. The outcomes from this project will help FDA to evaluate the potential carcinogenicity and mutagenicity of nitrosamine impurities in a timely fashion and to ultimately improve risk assessment of drug products.Proposed Project for TSIF FellowWe will develop machine learning models and validate the models with in vitro assays for assessing potential carcinogenicity and mutagenicity of nitrosamines in drug products. At FDA, the fellow will collect nitrosamines and their toxicological effects from FDA’s regulatory documents, public databases, and literature, develop predictive models of carcinogenicity and mutagenicity using machine learning algorithms such as decision forest [1] based on Mold2 descriptors [2] using chemicals curated from public databases and literature as the training set, and predict the potential carcinogenicity and mutagenicity of the curated nitrosamines using the developed models. At NCATS, the fellow will test carcinogenicity and mutagenicity using various in vitro cell-based qHTS assays [3] for the collected nitrosamines and will assess potential carcinogenicity and mutagenicity of nitrosamines in drug products by combining the results of machine learning model predictions and in vitro genotoxicity assays.Relevant PublicationsTong W, Hong H, Fang H, Xie Q, Perkins R. Decision forest: combining the predictions of multiple independent decision tree models. J Chem Inf Comput Sci. 2003 Mar-Apr;43(2):525-31. doi: 10.1021/ci020058s. PMID: 12653517.Hong H, Xie Q, Ge W, Qian F, Fang H, Shi L, Su Z, Perkins R, Tong W. Mold2, molecular descriptors from 2D structures for chemoinformatics and toxicoinformatics. J Chem Inf Model. 2008 Jul;48(7):1337-44. doi: 10.1021/ci800038f. Epub 2008 Jun 20. PMID: 18564836.Hsieh J, Smith-Roe S, Huang R, Sedykh A, Shockley K, Auerbach S, Merrick B, Xia M, Tice R, Witt K (2019) Identifying Compounds with Genotoxicity Potential Using Tox21 High Throughput Screening Assays. Chemical Research in Toxicology 32:1384-1401Developing Ipsc-Derived Macrophage Reporter Assays to Assess Immune Cell Responses to Nucleic Acid TherapeuticsFDA Mentor NameDaniela Verthelyi, M.D., Ph.D.Position and Organizational AffiliationChief, Laboratory of Immunology, CDERContact Information (email/telephone)daniela.verthelyi@fda.hhs.gov / 240-402-7450 NCATS Mentor NameMark Henderson, Ph.D.Position and Organizational AffiliationBiology Group Leader, Early Translation Branch, DPIContact Information (email/telephone)hendersonmj@mail.nih.gov / 301-827-1769Research Project SummaryThe last five years have seen a rapid increase in the number of nucleic acid-based therapeutics under development, in clinical trials, or approved for human use. This class of therapeutics includes antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and messenger RNAs (mRNAs). Nucleic acids have been reported to elicit off-target effects on innate immune cells via binding to pattern recognition receptors (PRRs), which can trigger inflammatory signaling cascades, and in some instances has been associated with fever-like symptoms or thrombocytopenia in clinical trials. These can be due to unintended effects of the oligonucleotides or impurities in the product. We propose to investigate and develop cell-based reporters of immune cell activation that can be utilized to better characterize nucleic acid-based therapeutics. Macrophages, which express PRRs and can recognize nucleic acids, are an essential component of the innate immune system that can rapidly respond to their environment. This project proposes to engineer iPSCs CRISPR/Cas9 technology and differentiate these cells to macrophage lineage to create bioreporters of inflammatory signaling, interferon inducible responses, and oxidative stress (e.g. heme oxygenase 1).Proposed Project for TSIF FellowFirst, the fellow would train at FDA/CDER, where (s)he would learn about drug product immunogenicity in the Verthelyi lab. The fellow will gain an understanding of current strategies to assess immune responses to active pharmaceutical ingredients and product impurities for new molecular entities and generic nucleic acid products. Second, the fellow would train at NCATS/DPI, where (s)he would continue learning about assay development and engage in optimization and implementation of the iPSC-derived macrophage assays. PRR activation will be investigated by comparing current assay technologies (immortalized cells, e.g. THP-1 RAW264.7, HEK293) with the newly generated reporter cells that are differentiated into macrophages (M0, M1, or M2 phenotype). The effects of nucleic acid therapeutics will be examined, with a focus on optimizing assay robustness and reproducibility. Key results would be validated in primary monocytes/macrophages from healthy blood donors. Overall, the goals of the proposed project are: 1) to pursue new strategies to predict innate immune responses to nucleic acid therapeutics (approved and investigational), and 2) to determine whether the toolset has predictive validity and provides utility for the examination of future clinical candidates.Measuring Generic Drug Impact on U.S. Health OutcomesFDA Mentor NamesMarkham Luke, M.D., Ph.D.Liang Zhao, Ph.D.Silvana Borges, M.D.Position and Organizational AffiliationMarkham Luke: Director, Division of Therapeutic Performance 1, CDERLiang Zhao: Director, Division of Quantitative Methods and Modeling, CDERSilvana Borges: Deputy Director, Division of Therapeutic Performance, CDERContact Information (email/telephone)markham.luke@fda.hhs.gov / 301-796-5556liang.zhao@fda.hhs.gov / 240-402-4468silvana.borges@fda.hhs.gov /301-796-0963NCATS Mentor NameJessica Binder, Ph.D.Position and Organizational AffiliationBiomedical Data Scientist, DPIContact Information (email/telephone)jessica.binder@nih.hhs.gov / 301-402-8953Research Project SummaryFDA uses Real World Data (RWD) and Evidence (RWE) to monitor postmarket safety and adverse events and to make regulatory decisions. The health care community is using these data to support coverage decisions and to develop guidelines and decision support tools for use in clinical practice. Medical product developers are using RWD and RWE to support clinical trial designs (e.g., large simple trials, pragmatic clinical trials) and observational studies to generate innovative, new treatment approaches.A generic drug is a medication created to be the same as an already marketed brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. These similarities help to demonstrate bioequivalence, which means that a generic medicine works in the same way and provides the same clinical benefit as the brand-name medicine. In other words, you can take a generic medicine as an equal substitute for its brand-name counterpart.While the impact of generic drugs may seem relatively obvious from potential cost-savings, the actual benefit to health care outcome for a given healthcare need may be less observable and complicated by the US healthcare delivery system and reimbursement plans. We anticipate that thru the use of RWD and RWE available to HHS, including FDA, CMS, and NIH that we may be able to discern the impact of certain generic drugs on health care outcomes.Proposed Project for TSIF FellowWe propose funding a fellow to help initiate and coordinate research on use of RWD to measure the impact of certain generic drug availabilities on health care outcomes. Such a fellow would be versed or very interested in econometrics and have an interest in drug access and supply. Three possible prongs to the project are listed below.Research report on generic drug utility and value added/subtracted in various healthcare areasDoes patient access to prescribed medications generally improve, or improve in specific areas?Do health outcomes concomitantly improve because a greater proportion of the patients can now afford to take certain medications? Are health outcomes maintained, or degraded?Identify areas that might have some controversies or clinical doubt about generic drug use – e.g. thyroid medications, inhaled drug products, topical drugs, anti-obesity peptide drugs?Explore whether RWE data can help us understand differential uptake of generic drugs, e.g. where prescribers instruct pharmacists to “dispense as written” or where patients feel that they are not responding the same way to a generic?Why do some patients use the brand when the generic is available? Managed care, pharmacy benefit management (PBM issues) vs. prescriber habit?Compare two drugs in similar clinical situation, but one with generic access and another without?Relevant PublicationsA new paradigm for topical generic drug products: Impact on therapeutic access - PubMed (nih.gov)Medication Cost-Savings and Utilization of Generic Inhaled Corticosteroid (ICS) and Long-Acting Beta-Agonist (LABA) Drug Products in the USA - PubMed (nih.gov)Patents And Regulatory Exclusivities On Inhalers For Asthma And COPD, 1986–2020 \| Health AffairsFrontiers \| Integrating Real-World Evidence in the Regulatory Decision-Making Process: A Systematic Analysis of Experiences in the US, EU, and China Using a Logic Model \| Medicine (frontiersin.org)Real world evidence (RWE) – a disruptive innovation or the quiet evolution of medical evidence generation? - PMC (nih.gov)JCI - Opportunities and challenges in using real-world data for health careComparative Effectiveness and Safety of Generic Versus Brand-Name Fluticasone–Salmeterol to Treat Chronic Obstructive Pulmonary Disease \| Annals of Internal Medicine (acpjournals.org)Developing Novel Strategies to Improve Adeno-Associated Virus (AAV) Vector for Gene TherapyTranslational Science Priority Area: Innovation in Gene Therapy Vector Manufacturing and Safety ImprovementFDA Mentor NameNirjal Bhattarai, Ph.D.Position and Organizational AffiliationLab Chief, TVBB/DC2/OCTHT/OTP, CBERContact Information (email/telephone)Nirjal.Bhattarai@fda.hhs.gov / 240-402-6834NCATS Mentor NamesElizabeth Ottinger, Ph.D.Venkata Mangalampalli, Ph.D.Position and Organizational AffiliationElizabeth Ottinger: Acting Director of the Therapeutics Development Branch, DPIVenkata Mangalampalli: Staff Scientist of the Therapeutics Development Branch, DPIContact Information (email/telephone)elizabeth.ottinger@nih.gov / 301-827-0969venkata.mangalampalli@nih.gov /301-761-6957Research Project SummaryAdeno-associated virus (AAV) vector-based gene therapies have shown great potential to treat many human diseases. Although AAV gene therapy has improved over the last decade, challenges in vector manufacturing and issues with unwanted immune responses to the AAV vectors themselves remain. The goal of this project is to develop novel manufacturing strategies to improve AAV vector quality, purity, and yield, while simultaneously reducing immunogenicity.Proposed Project for TSIF FellowIn this project, the fellow will work on one of these focus areas to improve AAV vector-based gene therapy.Focus Area 1: Characterization of host cell factors and improvement of AAV vector production The HEK293 cell line is commonly used for AAV vector production. While significant improvements have been made in vector design to improve production, very little is understood about impact of the host cell factors on AAV production. Previous studies have shown activation of antiviral and inflammatory factors in HEK293 cells during AAV production; however, their impact on vector production is unknown. In this project, the fellow will perform comprehensive assessment of factors present in HEK293 cells that affect vector quality, potency, and yield. Using a high-throughput chemical screening method that takes advantage of libraries of small molecule inhibitors, HEK293 factors that affect vector production will be identified. Once these factor(s) are identified, CRISPR/Cas system will be used to engineer a novel HEK293 cell line with these factor(s) knocked out for improved AAV vector production.Focus Area 2: Rational design of AAV capsids to reduce immunogenicity and anti-drug-antibody response Host immune responses to AAV vectors can cause adverse events such as compliment activation and organ toxicities as well as reduce efficacy of AAV vector-mediated gene therapy. Developing AAV vectors with reduced immunogenicity profiles, without affecting potency, would significantly improve the potential applications for AAV in gene therapies. In this project, the fellow will develop novel strategies to design AAV capsids to inhibit host immune responses. For example, fellow will perform studies to identify novel immune-inhibitory peptide(s) from other human viruses that are known to evade immune responses to cause persistent infection. Next, the fellow will engineer novel AAV capsids with these immune-inhibitory peptide(s) incorporated into the capsid. Fellow will perform studies to assess structure of novel capsids using computational and experimental methods. The immunogenicity, tropism and potency of newly designed capsids will be studied using primary human cells and 3D cellular models such as organoids in vitro and mouse models in vivo. In vivo assessment will include measurement of anti-AAV capsid T cell responses, antibodies against AAV capsids, and release of inflammatory cytokines in the serum following AAV administration.Focus Area 3: Development of stable HEK293 cell line for improved AAV vector production Currently, AAV vectors are produced in HEK293 cells by transient transfection of three plasmids: a) a helper plasmid that expresses adenovirus helper genes required for AAV packaging; b) a helper plasmid that expresses AAV Rep and Cap genes, which are required for genome synthesis and capsid formation; and c) a plasmid that expresses the payload (gene of interest). This method is inherently variable, a significant issue in the manufacturing process that contributes to lot-to-lot inconsistencies in vector production. To minimize the variability of transient transfection, the fellow will work on developing a variant HEK293 cell line that stably expresses either one or both of the helper plasmids required for AAV production. The fellow will then test the new cell line for AAV vector production and assess vector quality, purity, and potency. The fellow will also characterize the resulting cell line(s) by performing comprehensive “Omic” profiling of clones that are high vector producers and identify factors that impact productivity.Relevant PublicationsA short hepatitis C virus NS5A peptide expression by AAV vector modulates human T cell activation and reduces vector immunogenicity. Gene Therapy. 2021. PMID: 34759330The platform vector gene therapies project: increasing the efficiency of adeno-associated virus gene therapy clinical trial startup. Hum Gene Ther. 2020. PMID: 32993373Developing Analytical Methods for the Analysis and Evaluation of Human Growth Hormones and Biosimilar ProductsFDA Mentor NameKang ChenPosition and Organizational AffiliationResearch Chemist, CDERContact Information (email/telephone)Kang.Chen@fda.hhs.gov / 240-402-5550NCATS Mentor NamesChristopher LeClair, Ph.D.Dingyin Tao, Ph.D.Position and Organizational AffiliationChristopher LeClair: Director, Analytical Chemistry Core, DPIDingyin Tao: Lead, Mass Spectrometry Team, Analytical Chemistry Core, DPIContact Information (email/telephone)leclairc@mail.nih.gov / 301-480-9941dingyin.tao@nih.gov / 301-827-7176Research Project SummaryAs of March 2020, drug applications for certain biological products previously regulated under section 505 of the FD&C Act are now assessed and licensed under the 351(a/k) BLA pathway of the PHS Act. This regulatory transition enabled the possibility of new biosimilar applications for these products, which if approved, could reduce direct patient cost. Included in these regulated biological products are growth hormone drugs composed of the individual proteins or protein mixtures of human chorionic gonadotrophin (hCG), follicle stimulating hormone (FSH), luteinizing hormone (LH), human growth hormone (hGH) and human thyroid stimulating hormone (hTSH), which are naturally sourced from human urine or recombinantly expressed in various host cells. Biosimilar applicants need to provide appropriate data to demonstrate the protein higher order structure (HOS), oligomerization, glycosylation pattern, and bioassay results are of sufficient similarity between the biosimilar product and the innovator product. This necessitates developing modern analytical methods for successful analysis of complex protein mixtures specifically related to human growth hormones. The current proposal will evaluate similar growth hormone drug products with varied sources of production and formulation. Chemical, structural, and biological activity results will be analyzed holistically to assess correlations among them and identify characteristics of process features. Both the agency and biosimilar drug developers will benefit from these modern analytical approaches that would foster approval of future biosimilar hormone mixtures.Proposed Project for TSIF FellowUnder the guidance of mentors at the FDA and NCATS, the fellow will develop analytical methods for the analysis of human growth hormones, which are an important category of biological products. This will be achieved using various techniques and technology that include but is not limited to (i) fast protein liquid chromatography (FPLC), (ii) nuclear magnetic resonance (NMR), (iii) dynamics light scattering (DLS), (iv) mass spectrometry (MS), and (v) in vitro cell based bioassay. The fellow will conduct analysis and gather data on chemical and structural modifications (e.g., protein glycosylation, higher order structure, and oligomerization) and their effect in the bioassay of hormone drugs. The implementation of applicable biological product analysis in the drug regulatory field will offer greater assurance of drug quality and minimize potential adverse effects introduced through the use of biosimilar versions or changes to the manufacturing process. This research will provide CMC reviewers the necessary information, especially glycan and structural variation reflected in MS and NMR spectral data, to effectively evaluate physiochemical differences. The application of state-of-the-art analytical techniques at the FDA and NCATS for drug product quality characterization will be a unique regulatory research and development experience not available from other programs. Research results will be disseminated through professional meetings, peer-reviewed publications, and potential regulatory guidance.Relevant PublicationsChen K., Long D., Lute S., Levy M., Brorson K. & Keire D. Simple NMR methods for evaluating higher order structures of monoclonal antibody therapeutics with quinary structure. J. Pharm. Biomed. Anal. 2016 128, 398-407.Patil S., Keire D. & Chen K. Comparison of NMR and Dynamic Light Scattering for measuring diffusion coefficients of formulated insulin: implications for particle size distribution measurements in drug products. AAPS Journal 2017 19, 1760-1766.Peng J, Patil S., Keire D. & Chen K. Chemical Structure and Composition of Major Glycans Covalently Linked to Therapeutic Monoclonal Antibodies by Middle-Down Nuclear Magnetic Resonance. Anal. Chem. 2018 90, 11016-11024Xie T. et al. The ELISA Detectability and Potency of Pegfilgrastim Decrease in Physiological Conditions: Key Roles for Aggregation and Individual Variability, Scientific Report, 2020 10, 2476.Zhuo Y., Keire D. & Chen K. Minor N-glycan Mapping of monoclonal Antibody Therapeutics using Middle-down NMR Spectroscopy, Mol. Pharm. 2021 18, 441.Biel, T. et al, An etanercept O-glycovariant with heightened potency, Molecular Therapy - Methods & Clinical Development 2022 124, 135.Shipman J., Sommers C., Keire, D., Chen. K. & Zhu, H., Comprehensive N-Glycan Mapping using Parallel Reaction Monitoring LC-MS/MS, Pharm. Res. 2023 40, 1399.Wang, K. & Chen, K. Direct Assessment of Oligomerization of Chemically Modified Peptides and Proteins in Formulations using DLS and DOSY-NMR. Pharm. Res. 2023 40, 1329.Qiao X, Tao D, Qu Y, Sun L, Gao L, Zhang X, Liang Z, Zhang L, Zhang Y. Large-scale N-glycoproteome map of rat brain tissue: simultaneous characterization of insoluble and soluble protein fractions. Proteomics. 2011, 11(21):4274-8.Yan W, Zhong Y, Hu X, Xu T, Zhang Y, Kales S, Qu Y, Talley DC, Baljinnyam B, LeClair CA, Simeonov A, Polster BM, Huang R, Ye Y, Rai G, Henderson MJ, Tao D, Fang S. Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes. Nat Commun. 2023, 14(1):4798.Burns AP, Zhang YQ, Xu T, Wei Z, Yao Q, Fang Y, Cebotaru V, Xia M, Hall MD, Huang R, Simeonov A, LeClair CA, Tao D. A Universal and High-Throughput Proteomics Sample Preparation Platform. Anal Chem. 2021, 93(24):8423-8431.Investigate Neurotoxicity Associated With Poly-Substance Exposure Using Functional Neural Spheroid and Blood-Brain-Barrier Tissue Chip Models of Alzheimer’s and Parkinson’s DiseaseFDA Mentor NamesJohn Talpos, Ph.D.Hector Rosas Hernandez, Ph.D.Position and Organizational AffiliationJohn Talpos: Director of Division of Neurotoxicology, NCTRHector Rosas Hernandez: Staff Fellow, NCTRContact Information (email/telephone)john.talpos@fda.hhs.gov / 870-543-7329hector.rosas-hernandez@fda.hhs.gov / 870-543-7440NCATS Mentor NameEmily Lee, Ph.D.Position and Organizational AffiliationStaff Scientist, Team Lead, DPIContact Information (email/telephone)emily.lee@nih.gov / 301-480-7702Research Project SummaryThere is a need to integrate the use of functional neural models together with blood-brain-barrier assays to help predict toxic effects of compounds in healthy and disease brains. NCATS has previously established a method for generating functional neural spheroids with differentiated human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes, at cell type compositions mimicking specific regions of the human brain.We have demonstrated that these neural spheroids display spontaneous synchronous calcium oscillations, as measured with fluorescence biosensors or calcium dyes, with patterns that depend on the neuronal-type composition. We have also developed neural spheroids incorporating neurons genetically engineered with CRISPR-induced alleles associated with Alzheimer’s (AD; APOE4 and APP A673V) and Parkinson’s disease (PD; A53T SNCA) and shown that inclusion of neurons with these disease mutations changes calcium activity. FDA/NCTR has developed models of the blood-brain-barrier (BBB) and studied the effects of amyloid β-peptide (Aβ) on BBB function.Here, we propose to integrate the use of neural spheroids from NCATS and BBB chip models from FDA/NCTR to 1) investigate whether poly-substance exposures, including heavy metals, affect neuronal activity, neurotoxicity, and development of AD and PD disease relevant phenotypes, in healthy and diseased neural spheroid mimicking different brain regions (e.g. SN, PFC, and HPC) and containing immune cells like microglia; and 2) determine how this toxicity may be altered by incorporating the effects of selective compound passage or clearance measured in a BBB tissue chip microfluidics system, with or without AD and PD disease relevant perturbations.Proposed Project for the FellowThe TSIF Fellow will directly lead this project, as well as design and execute experiments, with mentorship from Dr. Emily Lee (NCATS), Dr. John Talpos (NCTR/FDA), and Dr. Hector Rosas Hernandez.At NCATS, the TSIF Fellow, he/she will be trained by Dr. Emily Lee (Team Lead) and Dr. Jiajing Zhang (current postdoctoral fellow). He/she will be trained to make neural spheroids and on high-throughput screening including small molecule screening and phenotypic assays, disease modeling, automation technologies, and data processing. We expect that the TSIF Fellow will utilize existing functional neural activity read-outs and develop novel, disease relevant assays that will be used to measure effects of chemical substances on neuronal activity and disease progression in the AD/PD neural spheroid models, including production/accumulation of Aβ, Tau, -synuclein, neuroinflammatory markers such as reactive oxygen species (ROS), and cell death.At NCTR/FDA, the TSIF Fellow will train on the development of a BBB models on a chip by Dr. Hector Rosas Hernandez. The TSIF fellow will also gain additional experience in developing assays related to neuronal viability and inflammation in BBB microphysiological systems, including the use of confocal microscopy, differentiation of lineage-specific cells from hiPSCs and performing toxicological research.The project outcomes will include the understanding of poly-substance exposure on neuronal activity, neurotoxicity and the development of neurodegenerative disease assay models, as well as validating their use as predictive platforms for preclinical drug testing. We anticipate at least 2 publications to result from this work.Relevant PublicationsStrong, C.E., Kundu, S., Boutin, M., Chen, Y.-C., Wilson, K., Lee, E., and Ferrer, M. (2022). Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening BioRxiv: The Preprint Server for Biology, May 4, 2022. Currently resubmitted to Comms Bio after peer-reviewed revisionsBoutin, M.E., Strong, C.E., Van Hese, B., Hu, X., Itkin, Z., Chen, Y.-C., LaCroix, A., Gordon, R., Guicherit, O., Carromeu, C., Kundu, S., Lee, EM, Ferrer M. (2022). A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids. SLAS Discovery S2472555222000089. https://doi.org/10.1016/j.slasd.2022.01.003.Rosas-Hernandez, H., Cuevas, E., Lantz, S. M., Paule, M. G., & Ali, S. F. (2018). Isolation and culture of brain microvascular endothelial cells for in vitro blood-brain barrier studies. Neurotrophic Factors: Methods and Protocols, 315-331.Cuevas, E., Rosas-Hernandez, H., Burks, S. M., Ramirez-Lee, M. A., Guzman, A., Imam, S. Z., ... & Sarkar, S. (2019). Amyloid Beta 25–35 induces blood-brain barrier disruption in vitro. Metabolic brain disease, 34, 1365-1374.Data-Driven Innovation and Regulation for Next-Generation DiagnosticsFDA Mentor NamesSara Brenner, M.D., M.P.H.Keith Campbell, M.D., Ph.D.Position and Organizational AffiliationSara Brenner: Chief Medical Officer; Associate Director for Medical Affairs; Director, Diagnostic Data Program, CDRHKeith Campbell: Director, FDA SHIELD Program, CDRHContact Information (email/telephone)Sara.Brenner@fda.hhs.gov / (240) 402-7533Keith.Campbell@fda.hhs.gov / (541) 977-7771NCATS Mentor NamesSam MichaelMarc Ferrer, Ph.D.Position and Organizational AffiliationSam Michael: Chief, Information Technology Resources Branch (ITRB), OAMMarc Ferrer: Senior Scientist, Director, 3D Tissue Bioprinting Lab, ETB, DPIContact Information (email/telephone)michaelsg@mail.nih.gov / (301) 827-7796marc.ferrer@nih.gov / (301) 480-9845Research Project SummaryThe FDA Diagnostic Data (DxD) Program is a collaborative enterprise supporting FDA’s mission-critical priorities, including:1) Developing innovative approaches for capture, harmonization, transmission, and analysis of diagnostic data originating from over the counter (OTC), point-of-care (POC), and lab-based diagnostic tests2) Expanding the quality, functionality, and utility of the diagnostic data ecosystem across multiple stakeholders and agencies3) Providing enhanced regulatory support and guidance to ensure that safe, effective, and accurate diagnostics from emerging and convergent technologies are first to market in the U.S.We are seeking a TSIF Fellow to join this exciting team and contribute to research and project development studying and deploying data analytics and creative new approaches to support innovation within FDA and with NIH NCATS. An important part of this work is a new program: Diagnostics Data & Evidence Ecosystem Platform (DEEP). It is an agile inter-agency program to build a regulatory sandbox for diagnostic data using leading edge technologies.The DxD Program serves as a model for how high-quality data from both conventional and unconventional sources, including real-world data (RWD), can be used to support regulatory decision-making across other medical product spaces. Executing on this visionary program of wide breadth and scale requires the support of diverse and talented group of people who are enthusiastic about taking a future-oriented approach to supporting FDA and CDRH’s mission. The members of the DxD Program bring together expertise in IVDs, microbiology, virology, medicine, public health, software, digital health, cybersecurity, information technology, and research and development.Proposed Project for TSIF FellowThe FDA Diagnostic Data (DxD) Program established a new, first-of-its-kind technology program at FDA with full-time staffing and significant funding with two specific focus areas – Digital Diagnostics [OTC/POC] and Semantic Harmonization and Interoperability Enhancement for Laboratory Data [SHIELD] – aimed at improving the quality, interoperability, portability, and utility of OTC, POC, and laboratory-based diagnostic data within and between institutions and individuals.The TSIF Fellow will primarily focus on DEEP a currently funded joint FDA-NIH NCATS project. The first deliverable for this project is building a functional EUA to 510(k) conversion module for regulatory submissions. DEEP will enable IVD device reviewers to leverage real-world evidence and data as part of the EUA to 510(k) conversion process for clearing COVID-related IVDs. We aim to reduce reviewer burden and improve review performance and quality by leveraging high quality data supplied by sponsors along with a variety of high-quality diagnostic data sources from DxD program partners and other federal agencies. These relationships with industry, academia, and federal agencies will create a robust network of powerful connections for the selected fellow and provide many opportunities for current and future learning, career, and research opportunities.DEEP is being built on the Palantir Foundry platform using proven and leading-edge capabilities including semantic search and machine learning. This enables us to move fast and deliver solid capabilities. It will pull together elements of the OTC/POC and SHIELD programs. We expect close partnership with NCATS for developing inter-agency programs and for their expertise in Palantir.Relevant PublicationsFDAEncoding laboratory testing data: case studies of the national implementation of HHS requirements and related standards in five laboratories \| Journal of the American Medical Informatics Association \| Oxford Academic (oup.com)Diagnostic Data Program \| FDADiagnostic Data Exchange (FDA) \| The Opportunity Project (census.gov)Clinical Genomic and Genetic Testing: Towards Data Standards for Analysis and Exchange NCATSDe-black-boxing health AI: demonstrating reproducible machine learning computable phenotypes using the N3C-RECOVER Long COVID model in the All of Us data repository.Vaccination Against SARS-CoV-2 Decreases Risk of Adverse Events in Patients who Develop COVID-19 Following Cancer Surgery.Metformin is Associated with Reduced COVID-19 Severity in Patients with Prediabetes.Issues with Variability in EHR Data About Race and Ethnicity: A Descriptive Analysis of the National COVID Cohort Collaborative Data Enclave.Assessing Disparities in COVID-19 Testing Using National COVID Cohort Collaborative.Higher hospitalization and mortality rates among SARS-CoV-2-infected persons in rural America.Multilevel determinants of racial/ethnic disparities in severe maternal morbidity and mortality in the context of the COVID-19 pandemic in the USA: protocol for a concurrent triangulation, mixed-methods study.Identifying who has long COVID in the USA: a machine learning approach using N3C data.The National COVID Cohort Collaborative (N3C): Rationale, design, infrastructure, and deployment.CURE ID: Expanding the Platform’s Capabilities to include Automated Extraction and Adverse Event ReportingFDA Mentor NamesHeather Stone, M.P.H.Suranjan De, M.S., M.B.A.Position and Organizational AffiliationHeather Stone: Health Science Policy Analyst (CURE ID Team Lead), Office of Medical Policy/Center for Drug Evaluation and Research (OMP/CDER)Suranjan De: Deputy Director, Regulatory Science Staff, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research (OSE/CDER)Contact Information (email/telephone)heather.stone@fda.hhs.gov / 301-283-1682Suranjan.de@fda.hhs.gov / 240-402-0498NCATS Mentor NameEwy Mathé, Ph.D.Position and Organizational AffiliationDirector of Informatics, DPIContact Information (email/telephone)ewy.mathe@nih.govResearch Project SummaryCURE ID is an FDA-NCATS collaboration that collects real-world drug repurposing information on rare diseases in case report forms (CRFs). The information is subsequently made publicly visible on an NCATS site through the CURE ID web and mobile applications (cure.ncats.io/). Many diseases, such as Balamuthia and angiosarcoma, are difficult to study and lack approved treatments. Analyzing aggregated treatment data for such diseases may help generate efficacy signals. The fellow will participate in the following CURE ID projects:Automate Manual Extraction – Currently, published cases from the literature are manually extracted into a CRF. This project will build tools that automate the extraction using Natural Language Processing and Machine Learning technologies (NLP/ML).Adverse Events CRF – The FDA adverse event reporting tool is not user-friendly and has not kept up with technological advancements (e.g., mobile apps) and there is interest from OSE in building off the CURE ID infrastructure to capture AEs.Modify the EDGE Tool - The EDGE tool has exponentially augmented the data extraction capacity of CURE ID by automatically extracting COVID-19 cases from electronic health records (EHR) into a CRF. This project will work with partners to modify the EDGE tool for use in sepsis, meningitis, and hyperemesis gravidarum.Explore and pilot a Hybrid CRF – The goal for this project is to combine the existing patient, clinician, and EHR extracted CRFs into one where data extracted from EHRs is supplemented with patient’s review and physician feedback, when possible, for incorporation into a hybrid CRF.Proposed Project for TSIF FellowThe outlined projects will require the fellow to apply their knowledge, learn new skills, generate data, and conduct various analyses:Automate Manual Extraction - The fellow will use informatics and clinical knowledge to explore existing tools and develop methods to identify and extract information from case reports in literature databases, then populate the CRF. They will analyze any gathered data to identify promising drugs for the targeted disease, enrich the CURE ID database with information about the drug, and investigate mechanisms of action. This may culminate in designing in vitro studies to be conducted at NCATS.Adverse Events CRF - The fellow will collaborate with FDA to design this CRF and alongside NCATS informatics, will implement it. Analysis of data gathered has potential to improve drug safety.Modify the EDGE Tool - The fellow will bridge the clinical and informatics sides of this project. The fellow would also have an opportunity to work with the Hopkins team to further develop the EDGE tool by identifying variables to be extracted for sepsis, meningitis, and hyperemesis gravidarum.Explore and pilot a Hybrid CRF – The fellow will help design and develop a hybrid CRF. They will investigate implementation of a Global Unique Identifier (GUID) to link EHR, patient-provided, and physician-provided information together while ensuring minimal identifiability.Importantly, all projects aim to expand the data being collected as part of CURE ID. For each project, landscape and use case-focused data analysis will be performed by the scholar to exemplify the utility of the data.Relevant PublicationsThe data from automation of manual extraction will provide the fellow with sufficient data to conduct analysis on disease(s) of their choosing. This data can also be combined with the clinician submitted, and patient submitted case reports on CURE ID for larger studies and publication.The fellow will be a significant part of creating new data infrastructure and informatics processes while modifying the EDGE tool and developing a hybrid CRF. They will have the opportunity to author several publications outlining the informatics structure of these projects and lessons learnt from developing novel tools.Prior publications related to the project include:Charles R, Milani B, Dagne DA, Oliver N, Ali B, Stone HA, Schito M, Tirupathi, R. Landscape Analysis to Identify Effective Drug Repurposing Candidates for the Treatment of Implantation Mycoses: Comparison of World Health Organization Survey Treatment Data and Published Case Reports on CURE ID. Poster Presentation at IDWeek 2023. Boston, MA. October 11-15, 2023.Farid T, Charles R, Tumas K, Stone HA, Tirupathi R. The landscape of infections caused by rare bacterial pathogens. Poster Presentation at IDWeek 2023. Boston, MA. October 11-15, 2023.Milani B, Dagne DA, Choi HL, Schito M, Stone HA. Diagnostic capacities and treatment practices on implantation mycoses: Results from the 2022 WHO global online survey. PLOS Neglected Tropical Diseases 2023 17(6): e0011443. https://doi.org/10.1371/journal.pntd.0011443Heavner, Smith F. PhD, RN1,2; Anderson, Wesley PhD3; Kashyap, Rahul MBBS, MBA4,5; Dasher, Pamela BA1; Mathé, Ewy A. PhD6; Merson, Laura7; Guerin, Philippe J. MD, PhD8,9; Weaver, Jeff MBA10; Robinson, Matthew MD11; Schito, Marco PhD1; Kumar, Vishakha K. MD, MBA12; Nagy, Paul PhD13. A Path to Real-World Evidence in Critical Care Using Open-Source Data Harmonization Tools. Critical Care Explorations 5(4):p e0893, April 2023. \| DOI: 10.1097/CCE.0000000000000893Adhikari SD, Chaudhuri S, Boodman C, Gupta M, Schito M, Stone H, Gupta N. Fosfomycin for Non-Urinary Tract Infections: a systematic review. Infez Med. 2023 Jun 1;31(2):163-173. doi: 10.53854/liim-3102-4. PMID: 37283634; PMCID: PMC10241401.Reema Charles, MBBS, MD and others (Stone H), 627. CURE ID as a Tool for Curating and Analyzing Drugs Used in COVID-19 Clinical Trials, Open Forum Infectious Diseases, Volume 8, Issue Supplement_1, November 2021, Pages S417–S418, https://doi.org/10.1093/ofid/ofab466.825Mili Duggal, MPH, PhD and others (Stone H), 546. Capturing Clinician’s Experiences Repurposing Drugs to Inform Future Studies During COVID-19, Open Forum Infectious Diseases, Volume 7, Issue Supplement_1, October 2020, Page S339, https://doi.org/10.1093/ofid/ofaa439.740Stone H. and others, 1380. Safety of Repurposed Drugs for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: An Analysis of Adverse Events Reported in the Literature, Open Forum Infectious Diseases, Volume 6, Issue Supplement_2, October 2019, Page S501, https://doi.org/10.1093/ofid/ofz360.1244Stone H, Paul P. Exploring the Range of Clinical Efforts to Identify Repurposed Drugs for Neglected Infectious Diseases, America Journal of Tropical Medicine and Hygiene, Volume 101, January 201, Page 349-349.Stone H. and others, Collaborative Use Repurposing Engine (CURE): FDA-NCATS/NIH Effort to Capture the Global Clinical Experience of Drug Repurposing to Facilitate Development of New Treatments for Neglected and Emerging Infectious Diseases, Oral Abstract and Poster Presentation at IDWeek San Diego, CA, 2017. Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S12, https://doi.org/10.1093/ofid/ofx162.030Sacks L, Stone H, Callahan L, et al. (NTD-RD Working Group of FDA and NCATS). Database of Repurposed Drugs to Treat Neglected Tropical Diseases: An FDA-NCATS Collaboration. Abstract and Poster Presentation at the American Society for Tropical Medicine and Hygiene (ASTMH) 163rd Annual Conference, Washington DC. 2013.Enhancing Intestinal Barrier Research through Integrative High-Throughput TEER Analysis and Mechanistic Elucidation for Intestinal Toxicity ScreeningFDA Mentor NamesSangeeta Khare, M.S., Ph.D.Kuppan Gokulan, Ph.D.Position and Organizational AffiliationSangeeta Khare: Principal Investigator/Research Microbiologist, Division of Microbiology, NCTRKuppan Gokulan: Principal Investigator/Research Microbiologist, Division of Microbiology, NCTRContact Information (email/telephone)sangeeta.khare@fda.hhs.gov / 870.543.7519Kuppan.gokulan@fda.hhs.gov / 870.543.7467NCATS Mentor NamesXin Xu, Ph.D.Elias Carvalho Padilha, Ph.D.Position and Organizational AffiliationXin Xu: Sr. Scientist, Director, Drug Metabolism and Pharmacokinetics (DMPK) Core, DPIElias Carvalho Padilha: Staff Scientist, DMPK Core, DPIContact Information (email/telephone)xin.xu3@nih.gov / 301.480.9844elias.padilha@nih.gov / 301.827.1813Research Project SummaryTransepithelial electrical resistance (TEER) is an in vitro method to measure the barrier function of cellular monolayers that has been widely utilized in biological research such as drug screening and more 1-5. The NCATS DMPK Core in partnership with Applied Biophysics developed the automated TEER96 device (https://www.biophysics.com/teer96.php) to increase the throughput of TEER measurements. The device also allows for the continuous detection of TEER values over time in a sterile and temperature-controlled environment. Given the gained functionality, a unique opportunity is presented to utilize this technology to live-monitor the impact of chemicals to cell monolayers cultured in transwell systems. The DMPK Core has conducted a screening of orally available toxins from the Tox21 library in Caco-2 intestinal cell monolayers while monitoring TEER over 72 hours (collaboration with Dr. Menghang Xia of NCATS). Preliminary data showed that several compounds caused concentration dependent monolayer disruptions measured by TEER; however, the mechanisms involved in this barrier disruption remain elusive. This project aims to expand the TEER screening of oral toxins to the intestinal monolayer model and elucidate barrier disruption mechanisms with the goal of developing a new gut toxicity screening paradigm.The project will leverage the NCATS expertise with the TEER96, high-throughput screening, and automation and, at the NCTR, the project will benefit from Dr. Khare’s expertise in gut biology and toxicology to unveil the mechanistic features of the gut barrier disruption by orally available environmental toxins. The data generated from this project will provide valuable information for FDA regulation and public health.Proposed Project for TSIF FellowThe selected Fellow will participate in developing a new gut toxicity screening paradigm. The Fellow will lead the development of high-throughput assay for the intestinal barrier monitoring using TEER and further investigate the molecular mechanism of the food grade toxins involved in the disruption of the intestinal epithelial layer. The Fellow will work 50% time at the NCATS and 50% time at the NCTR/FDA. The proposed work will be as follows:NCATS: Test the potential intestinal toxicity of compounds from the Tox21 10K compound library that may be orally ingested from food or water (collaboration with Dr. Menghang Xia of NCATS Tox21 Program). These test compounds include pesticides, antibiotics, fragrances, food coloring compounds that are usually present in food or water.NCATS will perform TEER96 screening in human epithelial (Caco-2) cells and share the data of TEER results with NCTR Collaborator. Samples (cell extracts) will be sent to NCTR for gene expression analysis and (supernatants) cytotoxicity measurement. After gene expression analysis at NCTR.NCTR: Complete cell extraction and perform gene expression on samples related to cell monolayer disruption, cell death, and other relevant mechanisms which can influence the observed TEER profile. Cytotoxicity measurements will be measured from supernatants. Data will be shared with NCATS.The Fellow will present experiment results at the monthly meeting and share the data with NCATS and FDA mentors. The Fellow will participate in data interpretation and writing scientific report(s) with TEER profiles and gene expression information to be considered for publication in a scientific journal.Relevant PublicationsGokulan K, Kolluru P, Cerniglia CE, Khare S. Dose-Dependent Effects of Aloin on the Intestinal Bacterial Community Structure, Short Chain Fatty Acids Metabolism and Intestinal Epithelial Cell Permeability. Frontiers in Microbiology 2019;10.Gokulan K, Kumar A, Lahiani MH, Sutherland VL, Cerniglia CE, Khare S. Differential Toxicological Outcome of Corn Oil Exposure in Rats and Mice as Assessed by Microbial Composition, Epithelial Permeability, and Ileal Mucosa-Associated Immune Status. Toxicological Sciences 2021;180:89-102.Hao HH, Gokulan K, Pineiro SA, et al. Effects of Acute and Chronic Exposure to Residual Level Erythromycin on Human Intestinal Epithelium Cell Permeability and Cytotoxicity. Microorganisms 2019;7.Orr SE, Gokulan K, Boudreau M, Cerniglia CE, Khare S. Alteration in the mRNA expression of genes associated with gastrointestinal permeability and ileal TNF- secretion due to the exposure of silver nanoparticles in Sprague-Dawley rats. Journal of Nanobiotechnology 2019;17.Williams KM, Gokulan K, Cerniglia CE, Khare S. Size and dose dependent effects of silver nanoparticle exposure on intestinal permeability in an in vitro model of the human gut epithelium. Journal of Nanobiotechnology 2016;14.Siramshetty V, Williams J, Nguyen T, et al. Validating ADME QSAR Models Using Marketed Drugs. Slas Discovery 2021;26:1326-1336.Williams J, Siramshetty V, Nguyen DT, et al. Using in vitro ADME data for lead compound selection: An emphasis on PAMPA pH 5 permeability and oral bioavailability. Bioorganic & Medicinal Chemistry 2022;56.Gokulan K, Mathur A, Kumar A, Vanlandingham MM, Khare S. Route of Arsenic Exposure Differentially Impacts the Expression of Genes Involved in Gut-Mucosa-Associated Immune Responses and Gastrointestinal Permeability. International Journal of Molecular Sciences 2023;24.Parajuli P, Gokulan K, Khare S. Preclinical In Vitro Model to Assess the Changes in Permeability and Cytotoxicity of Polarized Intestinal Epithelial Cells during Exposure Mimicking Oral or Intravenous Routes: An Example of Arsenite Exposure. International Journal of Molecular Sciences 2022;23.Skrzydlewski P, Twaruzek M, Grajewski J. Cytotoxicity of Mycotoxins and Their Combinations on Different Cell Lines: A Review. Toxins 2022;14.	TSIF fellows will be matched with NCATS/FDA mentors on projects.		Translational Science Interagency Fellowship Projects and Mentors	TSIF fellows will be matched with NCATS/FDA mentors on projects.		Translational Science Interagency Fellowship Projects and Mentors
18093	Translational Science Training at NCATS	Emily Lee and Atena Farkhondeh Kalat discuss cell results displayed on a microscope in the Therapeutics for Rare and Neglected Diseases Biology Lab at NCATS. (Daniel Soñé Photography)Developing the next generation of translational scientists is a priority area for NCATS. The NCATS Division of Preclinical Innovation (DPI) provides a variety of training opportunities for undergraduate, graduate and postdoctoral level trainees. DPI is our intramural research program, with research groups located in Rockville, Maryland — a few miles from the main NIH campus in Bethesda, Maryland.DPI scientists develop system approaches that improve the efficiency and effectiveness of the translation process. Examples include advancing new technologies to make preclinical research more predictive and efficient or de-risking potential drug targets or research projects to make them more attractive for commercial investment. More than 200 scientists from a variety of disciplines are responsible for advancing the diverse research portfolio of DPI. In addition to conducting cutting-edge laboratory research, DPI scientists collaborate with more than 250 research organizations worldwide.Collectively, these individuals participate in a team science environment in which each project brings together expertise in:Biology (biological and disease assay development)Automation and engineering (high-throughput screening robotics)Informatics and data analysisMedicinal and analytical chemistryTo learn more, download the NCATS Intramural Program Flyer, visit the Intramural Research web page, and see videos and stories from the perspectives of our fellows.Interdisciplinary InteractionsThe image below illustrates a great strength of the DPI training program: interdisciplinary interactions.On the left, the image shows that DPI research teams are organized around —Early Translational Branch (formerly NCATS Chemical Genomics Center), which includes 3D Tissue BiofabricationTherapeutic Development BranchChemical Genomics Branch, which includes Assay Development and Screening Technologies, Chemistry Technologies, Functional Genomics Laboratory, Stem Cell Translation Laboratory, and Toxicology in the 21st CenturyCore Facilities, including Informatics, Analytical Chemistry and Research ServicesDownload our fact sheets to learn more about the research teams.Many of these research teams use similar technologies, skills and expertise, shown on the right, to complete their projects, resulting in substantial collaboration among disciplines as depicted by the overlapping ribbons. The complementarity of expertise in DPI creates an enriching environment in which fellows learn multiple skills from domain experts and gain additional scientific and career mentorship.Organizational and collaborative structure of DPI. DPI research teams (left) are organized into specific branches and use a variety of technologies, skills and expertise (right) to complete research projects. The width of the ribbons represents the amount of effort contributed by each research team to a specific technology, skill and expertise. The significant overlap of the ribbons reflects the interdisciplinary collaboration that is ongoing at DPI.Learn more about NCATS’ onsite research groups:Biomedical Data TranslatorBridging Interventional Development Gaps (BrIDGs)Chemistry TechnologyEarly Translation BranchFunctional Genomics LabTherapeutics for Rare and Neglected Diseases (TRND)Toxicology in the 21st Century (Tox21)DPI Staff ProfilesLearn more about NCATS’ intramural research training opportunities.	Developing the next generation of translational scientists is a priority area for NCATS.	/sites/default/files/chemist3_900x400.jpg	Translational Science Training at NCATS	Developing the next generation of translational scientists is a priority area for NCATS.	/sites/default/files/chemist3_900x400.jpg	Translational Science Training at NCATS
18096	Intramural Research Training Opportunities	Division of Preclinical Innovation Translational Scientist Training Opportunities The NCATS Division of Preclinical Innovation (DPI) provides a variety of training opportunities for undergraduate, graduate and postdoctoral level trainees. At the conclusion of their training, fellows in DPI will — Understand translational science is an emerging field of research that aims to develop the evidence base for effective scientific and operational practices in translational research. Frame where their particular research project fits within the translational science spectrum and be able to describe their unique contributions to a multidisciplinary team. Identify the transition points for advancing this work from the preclinical to clinical and public health domains. Be familiar with a range of career paths available to individuals with experience in preclinical translational research and be prepared to successfully transition to one of these options through participating in the career and research planning activities during their training in DPI. Read more about translational science training at NCATS or download the DPI Intramural Training Program presentation. To learn about the DPI training experience from the perspective of a fellow, see our Perspectives from NCATS Intramural Research Fellows videos and stories. On this page, find information about the following opportunities: Summer Internship Program in Biomedical Research NCATS Gaining Research Equity and Advancement in Translational Sciences (G.R.E.A.T.S) Program Postbaccalaureate Intramural Research Training Award Program Graduate Partnerships Program NIH Medical Research Scholars Program Postdoctoral Training in NCATS Research Groups NIH Visiting Program Translational Science Interagency Fellowship Summer Internship Program in Biomedical Research NCATS participates in the NIH Summer Internship Program in Biomedical Research (SIP). The NCATS summer internship program provides 25 participants with a full-time research experience in all aspects of drug discovery through a focused research project in either chemistry, biology, biotechnology, or engineering. During a summer at NCATS, interns will engage in hands-on research, seminars, career talks and journal clubs designed specifically for summer fellows. At the end of the summer, interns will present their research at both the NCATS Summer Poster Day and the NIH Summer Poster Day. For more information, download the NCATS Summer Internship Program Flyer. Candidates for the summer internship are undergraduate students and recent graduates from undergraduate degree programs. Applicants can apply online from mid-November to March 1 each year. For more information on the NIH application process, watch the Applying to the NIH Summer Internship Program video. NCATS Gaining Research Equity and Advancement in Translational Sciences (G.R.E.A.T.S) Program The NCATS G.R.E.A.T.S Program provides a diverse pool of summer internship applicants with an avenue to enter the translational science workforce. The paid summer research internship experience provides participants with seminars and career talks designed to develop communication, critical thinking, career readiness, and leadership skills needed to thrive in translational sciences. Potential summer interns must apply through the NIH Summer Internship Program (SIP) in Biomedical Research. When completing the application, applicants should indicate NCATS as their IC of interest and be sure to address in their cover letter if they have unique circumstances, or come from a disadvantaged background. They should also send their application number directly to NCATSDPITrainEd@mail.nih.gov specifying the NCATS G.R.E.A.T.S Program in the subject line. For more information, download the NCATS G.R.E.A.T.S Program Flyer (PDF - 175KB). Postbaccalaureate Intramural Research Training Award Program Recent college graduates who are planning to apply to graduate or professional (medical/dental/pharmacy) school can spend one to two years performing full-time research at NCATS through the NIH Postbaccalaureate Intramural Research Training Award Program. Applications are accepted year-round on a rolling basis. To learn more about the application process, watch the How to Apply to the NIH Intramural Postbac Program video. In addition to benefiting directly from their work in an NCATS DPI research team, participants in this program benefit from DPI’s vibrant postbaccalaureate program, with a seminar series, professional development opportunities, and a strong network of peers and mentors. For more information, download the Postbaccalaureate Intramural Research Training Award Program Flyer. Graduate Partnerships Program NCATS participates in both the institutional and individual Graduate Partnerships Program, which is designed to attract Ph.D. students to the NIH Intramural Research Program for their dissertation research. Participants enjoy the academic environment of their host university and the extensive research resources of NCATS. The goal is to create a different kind of graduate experience that focuses on training the next generation of scientific leaders by emphasizing communication and collaboration skills, integration of information, and interdisciplinary investigation. For more information, download the Graduate Partnerships Program Flyer. NIH Medical Research Scholars Program NCATS participates in the NIH Medical Research Scholars Program, a comprehensive, yearlong research enrichment program designed to attract the most creative, research-oriented medical, dental and veterinary students to the Intramural Research Program of NIH. Applications are open from Oct. 1 to Jan. 8 for entrance in the following academic year. Postdoctoral Training in NCATS Research Groups Postdoctoral fellows are recruited to NCATS through a variety of Postdoctoral Programs at NIH to work on specific projects. They also have ample opportunities to collaborate with scientists, both within and outside of NCATS on additional projects. Postdoctoral fellows are expected to present the results of ongoing work at meetings (such as internal group meetings and national conferences) and submit their work for publication in peer-reviewed scientific journals. Postdoctoral fellows also gain professional skills and exposure to a variety of career paths through participation in the DPI training program, including monthly career talks, an annual fellows’ retreat and career development seminars. For more information, download the Postdoctoral Training and Education Flyer. Immediate openings are posted on the NCATS Job Opportunities page; however, potential applicants should directly contact the DPI scientists with whom they would like to work to inquire about openings. NIH Visiting Program The NIH Visiting Program provides opportunities for foreign scientists in Ph.D. programs or foreign scientists who have received doctoral degrees to train and conduct collaborative research at NIH, including at NCATS. Individuals interested in training and/or conducting research at NCATS should directly contact the DPI scientists with whom they would like to work to inquire about openings and become familiar with the NIH process for visiting scientist appointments. Translational Science Interagency Fellowship The Translational Science Interagency Fellowship (TSIF) program is a postdoctoral fellowship program jointly sponsored by NCATS and the U.S. Food and Drug Administration. The objective of the TSIF program is to train a cadre of postdoctoral fellows in translational and regulatory science. Download a flyer about the TSIF program or visit the TSIF web page to learn more about the program. Federal Background Check Selected candidates for any fellowship opportunity described above are subject to a federal background check, using Standard Form-85 (read SF-85). Section 14 of the form asks, “In the last year, have you used, possessed, supplied, or manufactured illegal drugs?” The question pertains to the illegal use of drugs or controlled substances in accordance with federal laws, even though permissible under state laws. Acceptance into all fellowship programs is conditional upon a successful background check. Contact Us To learn more about undergraduate, postbaccalaureate and postdoctoral training opportunities in DPI’s Intramural Research Program, please contact the Intramural Education and Training Director, Marcus Hodges, Ph.D. Featured Intramural Fellows Charting a New Path: NCATS Internship Helps Promising Student Soar — Bryan Queme, a 2018 summer fellow, describes his experience at NCATS. Unexpectedly Following a Translational Science Path — Rosita Asawa, a former NCATS postbaccalaureate fellow, details how her training at NCATS helped shape her future career goals.	NCATS offers a variety of onsite training opportunities in its Division of Preclinical Innovation.		Intramural Research Training Opportunities	NCATS offers a variety of onsite training opportunities in its Division of Preclinical Innovation.		Intramural Research Training Opportunities
17931	NIH Awards $35.5 Million to Use Tiny, Bioengineered Organ Models to Improve Clinical Trials’ Development and Design	A tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), a leading cause of sudden death from cardiac arrest in children and young adults, on a tissue chip. Scientists from Boston Children’s Hospital and Harvard University reprogrammed blood cells from a patient with a gene mutation linked to most cases of CPVT and prompted these cells to become stem cells. These in turn were made into cardiomyocytes (heart muscle cells) carrying CPVT mutations, which were seeded onto an engineered surface. The cells, shown in purple, lined up in a direction similar to how heart muscle is organized and beat together. (Sung Jin Park/Boston Children’s Hospital and Donghui Zhang/Harvard SEAS)September 29, 2020 Clinical Trials on a Chip researchers plan to build and test common and rare disease models to help improve the clinical trial process.Approximately 85% of late-stage clinical trials of candidate drugs fail because of drug safety problems or ineffectiveness, despite promising preclinical test results. To help improve the design and implementation of clinical trials, the National Institutes of Health has awarded 10 grants to support researchers’ efforts in using tiny, bioengineered models of human tissues and organ systems to study diseases and test drugs. One major goal of the funded projects is to develop ways to better predict which patients are most likely to benefit from an investigational therapy prior to initiating clinical trials. The awards total more than $6.9 million in the first year, and approximately $35.5 million over five years, pending available funds. They are administered through a new program, Clinical Trials on a Chip, which is led by NIH’s National Center for Advancing Translational Sciences (NCATS) in conjunction with several other NIH Institutes and Centers, including the National Cancer Institute, the National Institute of Child Health and Human Development, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.Tissue chips, or organs-on-chips, are 3-D platforms engineered to support living human tissues and cells and mimic complex biological functions of organs and systems. Tissue chips are currently being developed for drug safety and toxicity testing and disease modeling research, including on the International Space Station. Clinical Trials on a Chip is one of several initiatives that are a part of the NCATS-led Tissue Chip for Drug Screening program, which was started in 2012 to address the major gaps in the drug development process.The projects are organized into two phases. In the first phase, the grantees will develop tissue chip models of disease. They also will develop biological indicators from the chips that correlate with clinical condition and enable scientists to determine the progression of a disease and effectiveness of a therapy. In the second phase, the researchers will evaluate the usefulness of the disease models by testing candidate therapies and, in some cases, collaborating with pharmaceutical and biotech companies to compare patient results with that of the corresponding patient chips.Many of these therapies will be tested in tissue chips in parallel to patients in clinical trials. In one project, for example, scientists plan to develop a tissue chip model of two types of muscular dystrophy, a muscle-wasting disease, to study the effects of a promising drug candidate already being tested in patients. Another team of researchers plans to develop a bone marrow model to determine which patients with treatment-resistant prostate cancer that has spread to the bone might benefit from a new therapy that also is being tested in patients.The new grantees bring expertise in clinical trial design, disease biology, engineering, pharmacology, computational biology and more. They will study a range of common and rare diseases, such as prostate cancer, pediatric disorders, kidney disease, heart disease, fatty liver disease and a disease that causes premature aging as well as premature birth.“Our hope is to eventually impact the fundamental way we do clinical trials,” said Danilo Tagle, Ph.D., NCATS associate director for special initiatives, who oversees the program, along with scientific program manager Passley Hargrove-Grimes, Ph.D. “We want to see if tissue chips can be a useful platform in which to help researchers preempt some potential challenges with trials. The teams have to make sure the models are valid and show that data from tissue chips accurately reflect results in people. If tissue chip data can predict which patient populations might benefit the most from investigational drugs, this information could potentially improve clinical trial success rates.”The 2020 awardees are:Boston Children’s HospitalWilliam Pu, M.D., and Kevin Kit Parker, Ph.D. (Harvard University’s Wyss Institute for Biologically Inspired Engineering)Tissue Chips for Precision Treatment of Catecholaminergic Polymorphic Ventricular TachycardiaGrant number: 1UG3TR003279-01 Brigham and Women’s Hospital, BostonYu-Shrike Zhang, Ph.D.Clinical Trials on a Premature Vascular Aging-on-a-Chip ModelGrant number: 1UG3TR003274-01 Cedars-Sinai, Los AngelesClive Niels Svendsen, Ph.D.A Microphysiological Multicellular Organ-on-Chip to Inform Clinical Trials in FTD/ALSGrant number: 1UG3TR003264-01 Columbia University, New York City (two-year award)Angela M. Christiano, Ph.D.Clinical Trials in a Dish Using a Personalized Multi-Tissue Platform for Atopic DermatitisGrant number: 1UG3AR079297 Johns Hopkins University, BaltimoreDeok-Ho Kim, Ph.D., and David Alan Kass, M.D. Engineering Clinical Trials on a Chip for Dystrophin-Deficient Muscular DystrophyGrant number: 1UG3TR003271-01 Texas A&M University/Texas Engineering Experiment Station, College StationArum Han, Ph.D., and Ramkumar Menon, Ph.D. (University of Texas)Developing Extracellular Vesicle-Based Therapeutics Against Pre-Term Birth Through the Use of Maternal-Fetal Interface on a ChipGrant number: 1UG3TR003283-01 University of PittsburghD. Lansing Taylor, Ph.D., Jaideep Behari, M.D., Ph.D., and Alejandro Soto-Gutierrez, M.D., Ph.D.A Vascularized Patient-Derived iPSC Liver Acinus Microphysiological System as an Innovative Precision Medicine Platform for Optimizing Clinical Trial Design for Nonalcoholic Fatty Liver DiseaseGrant number: 1UG3TR003289-01 University of RochesterHani A. Awad, Ph.D., James L. McGrath, Ph.D., and Benjamin L. Miller, Ph.D. A Microphysiological System of Tendon Inflammation and Fibrosis for Drug Screening and Efficacy TestingGrant number: 1UG3TR003281-01 University of Washington, SeattleJonathan Himmelfarb, M.D., and Matthias Kretzler, M.D. (University of Michigan)Safety and Efficacy of Human Clinical Trials Using Kidney-on-a-Chip Microphysiological SystemsGrant number: 1UG3TR003288-01 University of Wisconsin, MadisonDavid J. Beebe, Ph.D. and Joshua Michael Lang, M.D. Mechanisms of Microenvironment Mediated Resistance to Cancer Cell Surface Targeted TherapeuticsGrant number: 1UG3CA260692-01Media Contact: info@ncats.nih.govAbout the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about NCATS, visit https://ncats.nih.gov.About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov.NIH…Turning Discovery Into Health®	The NIH awarded 10 grants administered through a new program led by NCATS called Clinical Trials on a Chip.	/sites/default/files/TCTM_CPVT_900x600_2.jpeg	Using Tiny, Bioengineered Organ Models to Improve Clinical Trials	The NIH awarded 10 grants administered through a new program led by NCATS called Clinical Trials on a Chip.	/sites/default/files/TCTM_CPVT_900x600_1.jpeg	NIH Awards $35.5 Million

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