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| 14320 | DIAMOND Portal Offers Research Training for All | Competency Domains for the Clinical Research Professional Sonstein, S.A., Seltzer, J., Li, R., Jones, C.T., Silva, H., Daemen, E. (2014, June). Moving from compliance to competency: A harmonized core competency framework for the clinical research professional (PDF - 259KB). Clinical Researcher. 28(3); 17-23. Well-run clinical trials require well-trained staff. The people who work on clinical studies often have backgrounds in nursing, pharmacology, or other fields and then learn to run studies on the job. Researchers supported by NCATS’ Clinical and Translational Sciences Awards (CTSA) Program recognized a need for high-quality training materials and realized that academic medical centers already are developing them. The DIAMOND Portal, launched in September 2018, brings these training materials together in one place. DIAMOND stands for Development, Implementation, and Assessment of Novel Training in Domain-based Competencies. The initiative began as a way to share materials developed at CTSA Program hubs, but now anyone can upload resources to the portal. "Part of the vision of the CTSA Program is to be the catalyst to help move all clinical and translational research forward, so we are all charged with disseminating what we do," said Vicki Ellingrod, Pharm.D., co-principal investigator for DIAMOND at the Michigan Institute for Clinical and Health Research. DIAMOND was created in collaboration with the CTSA Program hubs at The Ohio State University, University of Rochester, and Tufts University. The portal includes training materials in eight different competency domains, ranging from the specifics of running trials to more general topics, such as leadership and professionalism. The portal also includes assessments that study teams can use to check that staff members are adequately trained. In addition, research professionals can boost their careers by maintaining an electronic portfolio of their training materials through DIAMOND. More than 17,000 people have accessed the portal so far, including many from outside the United States. Read more about DIAMOND. | Diamond Portal Offers Research Training for All | Diamond Portal Offers Research Training for All | ||||||
| 14290 | NCATS-Supported Scientists Model Aging-Related Conditions in Space to Improve Human Health on Earth | Editor's Note: This announcement, which was originally posted on April 24, has been updated to reflect the May 4 launch date.April 24, 2019Organ-on-chip projects at the International Space Station aim to speed the development of treatments for kidney stones, arthritis and more.NCATS-supported researchers sent four projects into space to speed both the study of aging-related conditions and the development of treatments for them. The projects, which launched May 4 to the International Space Station National Lab (ISS National Lab) on a Falcon 9 rocket from Cape Canaveral, Florida, use miniaturized tissue chip systems to mimic conditions similar to aging and certain disease states that appear to be accelerated in microgravity and provide insights that could improve human health here on Earth.Each project is funded through the Tissue Chips in Space initiative, a collaboration among NCATS, NIH’s National Institute of Biomedical Imaging and Bioengineering and the ISS National Lab. The ISS National Lab and NASA partner to use the U.S. portion of the space station for research.Tissue Chips in SpaceA lung-bone marrow tissue chip in space will help researchers explore how the body fights infection. (Biolines Laboratory, University of Pennsylvania)Tissue chips are tiny, complex bioengineered 3-D models that mimic the structure and function of human organ systems, such as the heart, kidneys and lungs. Scientists use tissue chips to test the potential effects of drugs on those tissues and to study diseases."A high percentage of candidate drugs fail in early testing in part because the models used are ineffective in predicting what will happen in patients," said NCATS director Christopher P. Austin, M.D. "Tissue chips are designed to increase efficiency, lower costs and make better predictions — and fill a gap in the translational process of turning promising compounds into approved drugs that can help people."The unique environment of space is the key for addressing some current translational science challenges in studying disease. In just a short period of time in the reduced gravity of space, astronauts’ bodies experience certain changes. Many of these changes are similar to those that occur as we age, including altered immune systems, and loss of muscles and bones."Tissue chips in space provide a way to model various diseases of the aging process. Such models can be difficult or take a long time to develop here on earth but are greatly facilitated under microgravity, and scientists can use them to develop drugs that can prevent or slow down those diseases," said Danilo Tagle, Ph.D., associate director for special initiatives at NCATS. "Taking this technology into space is an unprecedented opportunity to use tissue chips for accelerating translational development of interventions for use here on earth to treat many aging-related diseases. In addition to the biological impact of the disease models, working with space payload developers speeds technological innovations, including automation and miniaturization of the instrumentations that support tissue chip technology."Projects in OrbitNASA astronaut Christina Koch assists with the kidney tissue chip project on board the International Space Station. (NASA)The Tissue Chips in Space projects will test the ability of the tissue chip technology to mimic how human organs work and reveal what effects microgravity has on tissue function. Each experiment, which will have a comparable experiment in normal gravity, will have direct clinical applications to health conditions we experience on Earth.The tissue chips on the May 4 launch to the International Space Station are:Lung and bone marrow chips: Scientists and engineers at Children’s Hospital of Philadelphia and the University of Pennsylvania have designed two individual tissue chips to mimic conditions in the lung and the bone marrow to understand the body’s response to infection. They will trace how the lung reacts to a bacterial infection, and separately, watch how the bone marrow turns on and mobilizes immune system cells to fight an infection. After this launch, investigators will link the bone marrow and lung systems on one chip. The work is directly relevant to how aging impacts our ability to fight infections.Kidney chips: University of Washington and UW Medicine researchers plan to use kidney tissue chip models to understand how microgravity affects kidney function. They hope to uncover new clues to the cause, prevention and treatment of aging-related conditions of kidney function, such as changes in vitamin D metabolism and formation of kidney stones.Chips modeling the blood-brain barrier: Scientists and engineers at the biotechnology company Emulate will examine the mechanics of the blood-brain barrier and what makes it more permeable under microgravity. The blood-brain barrier is key to protecting the brain from infections and toxins in the blood. New insights into how the barrier works (or malfunctions) may help in understanding and treating neurodegenerative and immune disorders.Bone and cartilage chips: Massachusetts Institute of Technology researchers will use a bone-cartilage model to better understand how these tissues and the immune system interact after a knee joint injury, which can lead to sometimes debilitating osteoarthritis. Their findings may help in the development of treatments, which are lacking.On the HorizonEach tissue chip project will fly into space twice. The initial group of tissue chips will remain on the ISS National Lab for about one month before returning to Earth. On a second mission planned for approximately 18 months later, these tissue chips will be used to test potential drug therapies on the biological processes observed during the initial mission. For example, scientists who use the bone-cartilage chip model to examine the effects of a joint injury and the accelerated development of osteoarthritis plan to use the model to test novel compounds and drugs on osteoarthritis development.In addition to informing the development of new drugs and therapies, the projects could enable wider use of tissue chips on the ground."These projects illustrate a transformational acceleration in tissue chip technology that could make systems turn-key and automated, portable, and accessible to more researchers and more attractive to businesses, including pharmaceutical companies," said Lucie Low, Ph.D., scientific program manager of the NCATS Tissue Chips for Drug Screening program, which includes the Tissue Chips in Space program.In less than two years, the scientific teams and engineers collaborated to shrink a room full of lab equipment into “plug-and-play” shoebox-sized packages that could accommodate space limitations, stand the stress of spaceflight and be operated by astronauts and pilots who don’t know the research.This is the second time that NIH-funded tissue chip experiments have flown into space. Late last year, researchers from the University of California, San Francisco sent an experiment into orbit that examined the relationship between aging and the immune system."Tissue Chips in Space is an incredibly exciting program involving teamwork across scientific disciplines and federal agencies," said Low, "and I'm excited to see it take off." | /sites/default/files/tissue-chips-in-space_1260x841.jpg | NCATS-Supported Scientists Model Aging-Related Conditions in Space to | /sites/default/files/tissue-chips-in-space_1260x841.jpg | NCATS-Supported Scientists Model Aging-Related Conditions in Space to | ||||
| 14203 | Working Together Is the Name of the Game at Rare Disease Day at NIH | April 4, 2019“You aren’t heard as much as you need to be, so you kind of feel left in the background,” said Tesha F. Samuels, a panelist at Rare Disease Day at NIH who shared her experience with sickle cell disease. As a child, she and her mother would go from hospital to hospital to find relief for her pain. “What if, in 1990, my mother and I had a Rare Disease Day, where we knew that there were excited scientists and patient advocates looking for us?”Ms. Samuels’ sentiments reflected those of many patients and families attending the 2019 Rare Disease Day at NIH on Feb. 28. NCATS and the NIH Clinical Center co-sponsor the yearly event to raise awareness about rare diseases and connect researchers, regulators, patients and patient families to advance research and efforts to develop therapies.NIH Clinical Center patient Tesha F. Samuels discusses her experience with sickle cell disease during the “No Disease Left Behind, No Patient Left Behind” panel session at Rare Disease Day at NIH on Feb. 28, 2019. (Daniel Soñé Photography)Panel discussions covered collaborative approaches to rare diseases research, registries, rare cancers and gene therapy/gene editing. They highlighted NCATS’ philosophy that to maximize progress in rare diseases research, investigators and patients must work together. And together they were, with a record audience of more than 650 in-person attendees and 1,200 webcast views of this year’s event.Learning from Patient Advocacy GroupsInvestigators and patient advocacy group (PAG) representatives on one panel shared how this collaborative approach works in the NCATS-led Rare Diseases Clinical Research Network (RDCRN). The Network currently comprises more than 20 consortia, each consisting of medical research centers working with PAGs to study several related rare diseases.For example, the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) studies eosinophilic diseases, in which eosinophils — a type of immune cell — build up in the digestive tract and damage the tissues. Eosinophilic diseases are painful and lifelong, and they can make it hard or impossible for people to eat many foods.One of the consortium’s PAG representatives, Ellyn Kodroff, started the Campaign Urging Research for Eosinophilic Disease (CURED) after her daughter was diagnosed with eosinophilic disease in 2003. She recalled the time researchers and doctors asked for her thoughts on a research project at her first consortium meeting. She wondered whether they would listen to her.Seema Aceves, M.D., Ph.D. (left), and Ellyn Kodroff speak about how researchers, doctors and patients can work together in rare diseases research. (Daniel Soñé Photography)“Right in front of me, they changed gears of where they were going with the research, because now they could understand the patients’ needs,” Ms. Kodroff said.In turn, Ms. Kodroff and other PAG representatives bring information on clinical trials to the patient community and explain the importance of participating.Translating Patients’ Stories into DataPatient registries can help record patients’ stories to aid researchers in understanding diseases, designing studies and even changing clinical care. These registries can contain medical details as well as information about patients’ experiences — such as their quality of life, priorities and needs — that test results may not capture.“Registries are a way for patient advocacy groups to take the stories within their community and use that as a tool to describe them in a way researchers, regulators and decision makers can understand and interpret,” said Eric Sid, M.D., M.H.A., presidential management fellow in the NCATS Office of Rare Diseases Research, who moderated a session on the use of patient registries.Emily Milligan, M.P.H., executive director of the Barth Syndrome Foundation, explained why the foundation created a registry in 2006. Barth syndrome is a rare genetic disorder that mainly affects boys and can cause problems with the heart muscle, the immune system or other parts of the body.Investigators used the foundation’s registry data to understand more about the syndrome and how it progresses over time. The registry was also an invaluable tool for engaging the Food and Drug Administration (FDA), including at a patient-focused drug development meeting last summer.Panelists discuss the power of harnessing patient data through registries at Rare Disease Day at NIH. From left to right: Jeanine D’Armiento, M.D., Ph.D.; Janet Maynard, M.D., M.H.S.; Emily Milligan, M.P.H.; Forbes Denny Porter, M.D., Ph.D.; and Eric Sid, M.D., M.H.A. (Daniel Soñé Photography)“The registry data corroborates what FDA heard in the patient testimonies, and that helps to accelerate its decisions around approval of drugs,” Ms. Milligan said.Ms. Milligan and the Barth Syndrome Foundation lent their experience when the precursor to NCATS was looking at how to help other patient organizations set up registries. NCATS built on this pilot project to create the Rare Diseases Registry Program (RaDaR), which provides advice and best practices for creating and managing a registry.Cancers Can Be Rare Diseases, TooCancer may not be the first thing that comes to mind when people think of rare diseases, but one in three to four people with cancer has a rare type. Rare cancers include, for example, all pediatric, brain and spinal cancers, as well as sarcomas, which affect connective tissues like bone, skin and fat. In addition, research and advocacy efforts for rare cancers are often grouped under efforts for more common cancers, at times leaving the rare cancer and wider rare disease communities disconnected. A panel on rare cancers, held at this year’s Rare Disease Day for the first time, sought to find ways for the two communities to work together more closely.“Rare diseases and rare cancers suffer from the same of lack of infrastructure, interest and money,” said Corrie Painter, Ph.D., associate director of Count Me In, an initiative in which cancer patients make their genomic data freely available to researchers looking to find new treatments. “If we could find common ground to build that infrastructure, then all of us could leverage it at the same time rather than reinvent the wheel.”One suggestion was to create common data models, which is a way of collecting information on patients that allows it to be used by others more easily. Another suggestion for improving research and awareness efforts in rare cancers was to educate both oncologists and patient advocates about clinical trials so that they could share the information with patients and improve clinical trial recruitment.Leaving No Patient Behind in Gene Therapy and Gene EditingNear the end of the day, the discussion turned to clinical trials of gene therapy and gene editing. In principle, these technologies could be applicable to many different genetic diseases. In a session entitled “No Disease Left Behind, No Patient Left Behind,” panel members talked about how to make gene therapy and gene editing trials available and accessible to as many rare disease patients as possible. A first step toward that goal is ensuring patients’ voices are heard.John F. Tisdale, M.D., participates in the “No Disease Left Behind, No Patient Left Behind” panel session at Rare Disease Day at NIH on Feb. 28, 2019. (Daniel Soñé Photography)“We really need to partner with the patients to figure out what is most affecting their lives and what they would like to see changed in the context of a clinical trial,” said John Tisdale, M.D., chief of the Cellular and Molecular Therapeutics Branch at NIH’s National Heart, Lung and Blood Institute. “We’ve been trying to do that in the sickle cell disease space, but I think that across the board, we should do better.”In sickle cell disease, a defective gene leads to misshapen red blood cells that get stuck in blood vessels, causing severe pain, stroke or other complications. A bone marrow transplant can cure the disease, but most patients do not have a matched donor. Several years ago, Tisdale launched a gene therapy clinical trial for patients with sickle cell disease. His sickle cell research was featured on 60 Minutes in March 2019.The gene therapy allows adults who do not have a matched donor to use their own bone marrow stem cells. Doctors remove the cells, add the correct gene, and put the cells back into the patient. The few patients who have undergone the procedure through the trial are now making healthy red blood cells. Ms. Samuels, who is one of these patients, provided her unique perspective on the panel.Another crucial issue for leaving no patient behind is understanding the barriers to taking part in a clinical trial for a gene therapy. Patients, family members and patient recruitment specialists on the panel discussed these challenges and possible solutions.Alone TogetherIn his closing remarks, NCATS Director Christopher P. Austin, M.D., reinforced the need to work as a team and bring together complementary expertise.“I hear every day how alone patients with rare diseases and their families can feel and how alone researchers studying rare diseases feel,” Dr. Austin said. “So let’s all be alone together and think about rare diseases as a gigantic and ultimately beautiful jigsaw puzzle.” | Working Together Is the Name of the Game at Rare Disease Day at NIH | Working Together Is the Name of the Game at Rare Disease Day at NIH | ||||||
| 14164 | NCATS Assay Recognized in Top Ten List of Innovative Scientific Achievements | Images of blood vessel “tubes” in the high-throughput screening assay for angiogenesis, developed by NCATS investigators.March 26, 2019As a cancerous tumor grows, it needs new blood vessels to deliver nutrients and remove waste. Several cancer drugs work by disrupting the process of growing new blood vessels — called angiogenesis — to attempt to starve the cancer. But the methods for finding new and potentially more potent angiogenesis blockers have drawbacks. Some approaches look at several angiogenesis proteins in a test tube, which represent just one aspect of blood vessel formation. Others more closely model the natural process but are not very reproducible or can only look at a handful of molecules at a time.NCATS scientists, led by Menghang Xia, Ph.D., developed a new test, or assay, to identify molecules that block angiogenesis in special screening plates the size of an index card. These plates and allow investigators to look at more than 1,500 molecules at once with robot. The Society for Laboratory Automation and Screening (SLAS) named this work one of the ten most innovative scientific achievements to appear in its journal SLAS Technology in 2018.The NCATS investigators used two types of human cells that grow into blood vessel “tubes” in a 1,536-well plate. Because one type of these cells is engineered to glow green, researchers can see how many tubes form and find drugs that reduce the number of tubes in the plate. The team tested the approach with the NCATS Pharmaceutical Collection and found both known and potential new anticancer drugs that block angiogenesis. Read more about their work in the June 2018 issue of SLAS Technology. | A scientific society honored NCATS scientists for creating a screening test to identify molecules that block the growth of new blood vessels. The test could be useful in cancer research. | /sites/default/files/slas_1260x630.jpg | NCATS Assay on Top 10 Scientific Achievements List | A scientific society honored NCATS scientists for creating a screening test to identify molecules that block the growth of new blood vessels. The test could be useful in cancer research. | /sites/default/files/slas_1260x630.jpg | NCATS Assay on Top 10 Scientific Achievements List | ||
| 14152 | Brigham and Women’s Hospital and NCATS Scientists Dial Up an Approach Against Out-of-Control Inflammation | March 22, 2019Inflammation is an important part of the immune system’s response to injury and infection. It signals the body to heal and repair damaged tissue and defend itself against invaders such as viruses and bacteria.Normally, inflammation is temporary; the body has a process to halt it. But when the process breaks down because of an aging immune system, genetic disorder, or other cause, inflammation can become chronic and can contribute to diseases, including some cancers, heart disease, rheumatoid arthritis and neurodegenerative disorders.Current anti-inflammatory drugs mostly target the chemical trigger that prompts inflammation to begin or increase. But NCATS scientists, working with investigators at Brigham and Women’s Hospital in Boston, are investigating a different strategy to fight inflammation. Instead of attacking what sets it off, they are trying to take advantage of the body’s ability to quiet it down. The scientists have identified compounds that can mimic the activity of chemicals called resolvins, which step up the body’s natural ability to regulate inflammation. The findings, reported in Cell Chemical Biology, open the door to a potential new approach to treat out-of-control inflammation.Resolvins reduce inflammation by reducing the activity of immune system cells that are called into action by infection or injury. Scientists think that mimicking the effects of resolvins might be useful in treating excessive inflammation and the diseases it can cause. But producing compounds that can mimic these effects has been difficult. Resolvins have complicated, unstable chemical structures and are short-lived; they exist only to shut down inflammation, and then they disappear.About six years ago, NCATS scientists Marc Ferrer, Ph.D., Noel Southall, Ph.D., and Juan Marugan, Ph.D., began collaborating with Charles Serhan, Ph.D., D.Sc., director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women’s Hospital. Serhan was studying resolvins and similar substances that had comparable effects to reduce inflammation. Serhan and colleagues first discovered resolvins in 2002. Since then, his lab has advanced much of the understanding of the way resolvins work on immune cells through chemical docking stations called receptors. This interaction sends out a flood of chemical signals telling the immune system to stand down and naturally reduce inflammation. Human resolvin receptor shown with several attached molecules represented in green, blue, red, cyan, violet and magenta. Each can potentially turn on anti-inflammatory activity.Serhan found that a type of resolvin called resolvin D1 reduced inflammation in the nervous system and worked through a protein, GPR32, which is a receptor type called a G protein-coupled receptor. Other types of resolvins work through different receptors. Harnessing the body’s ability to control neurological inflammation could help treat spinal injury, stroke and Alzheimer’s disease.“It’s very appealing,” said Ferrer. “For neurological disorders, such as spinal injury or stroke, inflammation makes the neurological damage worse. We want to explore how controlling its resolution can help with disease treatment.At the same time, a better understanding of resolvins was needed.Serhan approached NCATS for help finding other molecules that were more stable than resolvins but could carry out the same function. Ferrer, Southall, Marugan and their NCATS colleagues used a technique called high-throughput screening to sort through more than 48,000 candidate compounds at the same time. The screening used a series of tests to look for molecules that could activate human GPR32.The team identified four compounds that had the most potential to turn on the body’s mechanism to reduce inflammation. Two are known molecules, and the other two have novel chemical structures. Serhan and his colleagues confirmed the anti-inflammatory and inflammation-resolving activity of the compounds in separate tests.“It’s the first time anyone has had synthetic molecules that could potentially modulate this receptor,” Marugan said, adding that the findings have helped explain the effects of resolvins and similar molecules. “This provides an opportunity to develop a new kind of drug to reduce inflammation.”According to Marugan, the work established an approach that researchers can use to discover and develop better candidate drugs more efficiently. At the same time, studying molecules that can reduce inflammation allows NCATS scientists to gain a better understanding of the intricate relationship between inflammation and the immune system.“The next step would be for medicinal chemists to further optimize and make these four molecules more specific, potent and drug-like,” Marugan said. “These molecules are starting points for drugs, and further testing will be needed.”The Brigham-NCATS group would still like to better understand the molecular bases of how GPR32 interacts with resolvins and other chemicals and how this interaction affects the chemical cues sent to immune cells to halt inflammation. | Scientists at Brigham and Women’s Hospital collaborated with NCATS high-throughput screening experts to develop a different approach against inflammation. | /sites/default/files/inflamation_1260x630.jpg | Understanding Out-of-Control Inflammation | Scientists at Brigham and Women’s Hospital collaborated with NCATS high-throughput screening experts to develop a different approach against inflammation. | /sites/default/files/inflamation_1260x630.jpg | Understanding Out-of-Control Inflammation | ||
| 14140 | Opioids Increase the Risk of Pneumonia | E. Jennifer Edelman, M.D., M.H.S., and Maricar Pendon, RN, of Yale University School of Medicine, confer about a patient. (Yale University Photo/Robert Lisak)March 18, 2019Opioids are often the only kind of medication that works for severe pain, but they can lead to addiction. Now, new NCATS-supported research suggests another danger associated with opioids: They increase the risk of pneumonia that is severe enough to warrant hospitalization. The research, led by E. Jennifer Edelman, M.D., M.H.S., from the Yale School of Medicine, was published in JAMA Internal Medicine.Edelman had read about research showing that opioids could suppress the immune system in the lab, and she wanted to know whether that was true in the community too. She was particularly interested in people with HIV, many of whom take opioids for pain. She and her colleagues turned to the Veterans Aging Cohort Study, a long-term study of people with and without HIV who receive care at U.S. Department of Veterans Affairs hospitals. The team compared more than 4,000 people who were hospitalized for pneumonia with more than 20,000 who were not, analyzing data that included opioid use. The work was supported in part by the Yale Center for Clinical Investigation, the Clinical and Translational Science Awards (CTSA) Program hub at Yale. The National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism also supported the research.People who received prescription opioids had a higher risk of pneumonia, and risk increased with higher doses of opioids. Research has suggested that some opioids — including codeine, morphine and fentanyl — suppress immune cells more than others; people who took those opioids were more likely to get pneumonia than people who took less immune-suppressing opioids such as oxycodone. People with HIV appeared to be more susceptible to pneumonia.“Fortunately, health care professionals are paying a lot more attention to careful and safer opioid-prescribing practices,” Edelman said. She said that her research suggests that people taking opioids should also get an annual flu shot and, if relevant, the pneumonia vaccine; should never smoke; and should quickly seek medical care if they have symptoms of pneumonia.Read more about the research from Yale University. | Research, supported in part by the CTSA Program, suggests that opioids can increase a person’s risk for pneumonia that is severe enough to warrant hospitalization. | /sites/default/files/yale_opioid_1260x630.jpg | Opioids Increase the Risk of Pneumonia | Research, supported in part by the CTSA Program, suggests that opioids can increase a person’s risk for pneumonia that is severe enough to warrant hospitalization. | /sites/default/files/yale_opioid_1260x630.jpg | Opioids Increase the Risk of Pneumonia | ||
| 14029 | Researchers Convene to Take Stock and Take Action in the Opioid Crisis | .highlighttitle { text-align: center; font-size: 24px; font-weight: bold; margin-bottom: 0.5em; } div.quotetext { margin-right: 1em; margin-left: 2em; } March 28, 2019In a large lecture hall, leading pain and addiction researchers watched a video of zebrafish swimming in a tank. The fish swam back and forth over a small square, triggering the release of hydrocodone, an opioid prescribed for pain, into the tank. These zebrafish were showing some of the same signs of addiction that humans exhibit. These included taking more hydrocodone over time and engaging in risky behavior to get it, explained Randall Peterson, Ph.D., a chemical biologist at the University of Utah.NCATS Director Christopher P. Austin, M.D. (right), talks to George Koob, Ph.D., Director of the National Institute on Alcohol Abuse and Alcoholism (left), and Peter Kalivas, Ph.D., professor and chair, department of neuroscience, Medical University of South Carolina (center), and fellow speaker at the Opioid Crisis and the Future of Addiction and Pain Therapeutics: Opportunities, Tools, and Technologies Symposium, during a break. (Image Caffeine Photography, LLC Photo/Chia Chi Charlie Chang)“What does risky behavior in a fish look like?” an audience member asked. Peterson clarified that fish usually avoid shallow areas of the tank where predators may lurk. However, zebrafish will venture into the shallow area if it is the only way to release more of the drug. Peterson will be able to use the shallow water test to look for new drugs that stop addictive behaviors in the fish — and, hopefully, to develop new therapies for addiction in humans.This test was one of many innovative approaches to finding new treatments for addiction or pain highlighted by researchers at The Opioid Crisis and the Future of Addiction and Pain Therapeutics: Opportunities, Tools, and Technologies Symposium in February 2019. NCATS co-hosted the two-day symposium with the National Institute on Drug Abuse (NIDA) and the National Institute of Neurological Disorders and Stroke (NINDS) as part of the Helping to End Addiction Long-termSM Initiative, or NIH HEAL InitiativeSM, a trans-NIH effort to address the opioid crisis through science.“This special meeting brought together the two sides of this scientific and medical and public health problem: the addiction and overdose side and the pain side,” said Christopher P. Austin, M.D., NCATS director, in his welcoming remarks. “We hope it will lead to new insights that otherwise wouldn’t happen.”Symposium participants discussed why it has been so difficult to find effective treatments for pain or addiction and highlighted innovative approaches to make inroads into the opioid crisis. But the urgency of the crisis, with more than 70,000 deaths in the United States last year, remained front and center in participants’ minds.Kurt Rasmussen, Ph.D., Director of the Division of Therapeutics and Medical Consequences at NIDA, gives a summary of the first day of the symposium. (Image Caffeine Photography, LLC Photo/Chia Chi Charlie Chang)“I can say without hyperbole that people are dying and families are torn apart because of addiction, and the people in this room have the ability to help,” said Kurt Rasmussen, Ph.D., Director of the Division of Therapeutics and Medical Consequences at NIDA and co-organizer of the symposium. “As a result of this symposium, think, ‘What will I do differently to help in this crisis?’ What new experiment will you do? What new collaboration or grant or technique will you pursue?”Think Differently: New Assays and ApproachesMost people first encounter an opioid when their doctor prescribes a painkiller. Prescription opioids attach to opioid receptors in the brain, similar to a key inside a lock. This turns the receptors on, which tells the brain to block the sensation and awareness of pain. The problem is that the receptors are located in the areas of the brain that inhibit breathing — which can lead to death from an overdose — and in the main reward center of the brain, making opioids highly addictive. In addition, individuals who use opioids long-term will eventually develop a tolerance to the effects of the drug.Researchers are working to develop new treatments for chronic pain that are not addictive. Some are looking at ways to turn on the opioid receptors in a way that blocks pain but doesn’t affect breathing or reward signaling. Others are targeting alternative opioid receptors that are not located in the reward center of the brain.Many researchers called for consideration of radically different approaches to therapy development. In his keynote talk at the symposium, Clifford Woolf, Ph.D., a neurobiologist at Boston Children’s Hospital, discussed why the target-based approach has not worked well. Woolf believes that many genes contribute to pain. A drug that blocks multiple proteins, which these genes code for, may be more effective than a drug targeting a single protein. To find the genes involved in pain, he and others called for large genetic studies on people who have chronic pain. Such studies, which have been done for diseases like asthma and depression, would help identify new drug targets for pain.Woolf and others at the symposium want better assays (tests) using human cells to mimic pain. For example, researchers can take skin or blood cells from a patient and reprogram them to become induced pluripotent stem cells (iPSCs) that can become other kinds of cells, including pain-sensing nerve cells. When these nerve cells are activated, they send electric signals to the brain that translate to pain. Woolf can measure this activity and test for molecules that reduce it. He highlighted how researchers used this approach to correctly predict whether a patient would respond to a pain treatment.“This is what precision medicine can be about,” Woolf said. “I know NCATS is devoting efforts to utilize this, and I think it’s going to be transformative.”Venetia Zachariou, Ph.D., a researcher at the Icahn School of Medicine at Mount Sinai, discusses a strategy to reduce pain signaling by targeting proteins that control the function of the opioid receptor. This strategy may lead to a treatment that blocks pain without affecting breathing or causing addiction. (Image Caffeine Photography, LLC Photo/Chia Chi Charlie Chang)Better Animal ModelsProblems with current animal models of pain are another reason that promising pain treatments fail during clinical trials, said Jeffrey Mogil, Ph.D., a pain researcher at McGill University.Mogil highlighted a significant issue in preclinical research: Around 70 percent of pain patients are women, yet just a couple of years ago, Mogil found that 79 percent of animal studies published in Pain looked only at males. That changed when NIH established a policy requiring NIH-funded researchers to include both sexes in animal studies.Jeffrey Mogil, Ph.D., discusses differences in pain signaling between men and women. (Image Caffeine Photography, LLC Photo/Chia Chi Charlie Chang)Now researchers are beginning to see what Mogil saw: The biology of pain is different in men and women. For example, Mogil said, about 10 years ago, scientists discovered that immune cells in the brain and spinal cord called microglia are important for pain signaling — but it turns out this is true only in male rats. Differences like this, which investigators are only beginning to understand, may explain why some pain treatments work better for men or women.Next Steps and Taking ActionDuring the last session of the symposium, NCATS, NIDA and NINDS staff highlighted opportunities for funding and research collaboration, as well as resources to help researchers take those next steps. One such resource is NCATS’ Assay Guidance Manual, which inspired the symposium. The manual is a free online guide for developing rigorous assays for drug discovery. NCATS is currently compiling new tools, methodologies and technologies for pain and addiction research for the next update of the manual.“There is tremendous urgency to help the many people dying of overdose and suffering from pain as we speak,” Austin said in his closing remarks. “I truly believe we can tackle this crisis, but we have to think about and do our science differently.” | NCATS co-hosted a two-day symposium in February 2019 that highlighted key challenges and innovative approaches in the preclinical drug development process for pain medications. | /sites/default/files/19-0228_NCATS_heal-sym-2_1260x630.jpg | Researchers Convene to Take Stock and Take Action in the Opioid Crisis | NCATS co-hosted a two-day symposium in February 2019 that highlighted key challenges and innovative approaches in the preclinical drug development process for pain medications. | /sites/default/files/19-0228_NCATS_heal-sym-2_1260x630.jpg | Researchers Convene to Take Stock and Take Action in the Opioid Crisis | ||
| 13999 | NCATS Spearheads a New Resource for Natural Products | The illustration depicts the wide geographic distribution of contributions from scientists to the Canvass library of natural products. The box at the top represents a plate with wells in which many individual experiments are conducted.March 23, 2019Natural products have long been used as therapies for cancer and infectious diseases, in addition to being treatments for cardiovascular disease, pain and inflammation. Academic laboratories and companies, however, often lack the resources or assays (tests) to evaluate the potential utility of natural products, and many important chemicals produced or isolated by researchers remain untested for biological activity.To better realize these chemicals’ potential medical use, NCATS researchers invited academic and industry scientists around the world to submit natural products for evaluation. NCATS scientists subsequently examined the biological activity of 346 such compounds through 50 assays to evaluate the compounds’ possible uses in treating a variety of diseases; the findings now make up the Canvass library of natural products. The researchers, led by Matt Hall, Ph.D., and Jason Rohde, Ph.D. (now with the Walter Reed Army Institute of Research), described this pilot effort in the American Chemical Society’s ACS Central Science.“Many drug companies today are moving away from using natural products as starting points in developing new medicines,” said Kanny Wan, Ph.D., a research scientist at NCATS who was also involved in the project. “We want to provide a publicly available platform to help fully characterize the biological activities of known natural products, a tool that doesn’t quite exist today. We’re hoping that the use of Canvass will lead to new therapies for diseases.”The researchers found some compounds with unexpected biological activities. For example, 2-cathafoline, a plant product, was discovered to have calcium-stabilizing effects, which could have potential use in treating cardiovascular diseases and diabetes. Piperine, a compound in pepper, could affect enzymes involved in metabolizing drugs.Version 2.0 of Canvass is planned, though the questions it will address and the data it will house remain to be determined. For more information, see https://tripod.nih.gov/canvass/. | Canvass, a screening library for natural products, was created by NCATS to uncover the potential medical use of these compounds and enable the creation of new treatments for diseases. | /sites/default/files/canvas_1260x630.jpg | NCATS Spearheads a New Resource for Natural Products | Canvass, a screening library for natural products, was created by NCATS to uncover the potential medical use of these compounds and enable the creation of new treatments for diseases. | /sites/default/files/canvas_1260x630.jpg | NCATS Spearheads a New Resource for Natural Products | ||
| 13840 | NCATS ASPIRE Design Challenges Questions and Answers | What is the NIH HEAL (Helping to End Addiction Long-termSM) Initiative? What are the NCATS ASPIRE Design Challenges for Translational Innovation in Pain, Opioid Use Disorder and Overdose? What is a prize competition? What are some advantages to using the prize competition mechanism? May non-U.S. citizens and/or non-permanent residents participate in the challenge? May federal employees participate in the challenge? Is an account with challenge.gov required to compete, and how do prospective participants set up such an account? How do prospective participants with existing challenge.gov accounts register for this challenge? What will be the method of payment? How will prizes be awarded? May participants fund development of submissions with federal funds? What are the options for participating in this challenge without using federal grants? May a participant’s company (a for-profit private entity) participate? How are entries evaluated and winners selected? Who are the technical advisory panelists or subject matter experts (SMEs)? Who are the judges? May entrants participate on multiple teams? May a participant submit more than one solution per challenge? If so, how distinct do the solutions need to be? May entrants respond to multiple challenge areas? Or is it best to consolidate and respond to the challenge for the overall solution that comprises two or more areas (Challenge 5)? What information should be included in an entry? May an entrant’s biographical sketch exceed five pages? What should be included in the biographical sketch? When should teams form, and what is NCATS’ level of involvement with the teams? Are preliminary data required for the design solutions? Are participants required to use a particular data set? May participants ask additional questions? Are program staff available to discuss scientific or technical questions by phone? NEW (April 4, 2019): What are included in matching funds or in-kind contributions? NEW (April 4, 2019): Is there a minimum amount of matching funds required to enter the competition? NEW (April 4, 2019): How should a prospective participating company (for-profit private entity) document the matching funds? NEW (April 4, 2019): When is documentation of matching funds required? NEW (April 4, 2019): Will applications to advance in vivo biological assays be considered? NEW (April 4, 2019): For the envisioned reduction to practice stage, will winners of the Design Challenges be required to work with each other? NEW (April 4, 2019): Does NCATS have a video where applicants can learn more? What is the NIH HEAL (Helping to End Addiction Long-termSM) Initiative? The NIH HEAL (Helping to End Addiction Long-term SM) Initiative is a trans-agency effort to address the national opioid epidemic. The initiative will bolster research to improve treatments for opioid misuse and addiction and enhance pain management. More information can be found here: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative. What are the NCATS ASPIRE Design Challenges for Translational Innovation in Pain, Opioid Use Disorder and Overdose? Through the NCATS ASPIRE Design Challenges, NCATS aims to develop innovative and catalytic approaches to help solve the opioid crisis through development of next generation non-addictive analgesics with new chemistries, data-mining and analysis tools and technologies, as well as biological assays that will revolutionize discovery, development and preclinical testing of new and safer treatments of pain, opioid use disorder and overdose. For Stage 1, NCATS is asking for innovative ideas to be submitted as concept proposals. For envisioned Stage 2, NCATS plans to ask for data showing development of prototypes. Stage 1: Design Challenges; December 31, 2018 to May 31, 2019 Concrete, tangible concept proposals $500,000 total prize per challenge; may be split among multiple winners After the winners are announced, they will be invited to travel to NIH to present their ideas. The goal at this meeting would be to identify collaboration opportunities with other winners for the envisioned Stage 2. Stage 2: Reduction-to-practice (envisioned follow-on challenge); Expected kick-off Fall 2019 Open to all eligible innovators. Stage one winners are encouraged to continue to the reduction-to-practice stage. New teams with innovative ideas will be allowed to enter the challenge at this stage. What is a prize competition? For a prize competition, or “challenge,” a monetary award is offered to a winning participant(s) whose solution meets the judging criteria. Success depends on meeting the challenge’s defined scientific goals. The America Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science Act (America COMPETES Act) is the original prize authority. The American Innovation and Competitiveness Act (AICA) (PDF - 362KB) updated this federal prize competition authority in December 2016 under the Science Prize Competition Act. In addition to stimulating innovation that has the potential to advance the agency’s mission, these pieces of legislation encourage public-private partnerships and commercialization of final products. What are some advantages to using the prize competition mechanism? A prize competition provides the best means of achieving the objectives of the NCATS ASPIRE Program because it addresses the intractable problem of transforming synthetic chemistry from an empirical endeavor to a predictive undertaking. While certain capabilities exist under other funding instruments available to NCATS, the constellation of capabilities required to reward and spur the degree of innovation, collaboration and transparency requisite to advance the NCATS ASPIRE Program, at a pace appropriate to address a public health emergency, is available only under prize authority. Critical to the success of the program are several capabilities: engage diverse and non-traditional stakeholders, including individuals unaffiliated with an organization, who may not otherwise take advantage of NIH opportunities (e.g., NSF, DARPA and NIST grantees), as well as citizen scientists; ensure high visibility to ignite and sustain interest and momentum through broad advertisement using the federal challenge.gov platform to augment traditional means (e.g., the NIH Guide to Grants and Contracts); jumpstart the effort by rapidly identifying successful designs to move toward the immediate scientific objective in the context of the opioid crisis and simultaneously obtain generalizable information to disseminate due to NCATS’ ability to immediately share winning designs with the public; and mitigate risks by awarding cash prizes for completed designs instead of providing funding for yet-to-be-developed designs. May non-U.S. citizens and/or non-permanent residents participate in the challenge? Yes. While non-U.S. citizens and non-permanent U.S. residents are not eligible to win a prize (in whole or in part) under the America COMPETES Act, NIH generally permits non-U.S. citizens and non-permanent U.S. residents to register for and participate in NIH challenges. Such individuals may, for example, participate as part of a team that satisfies the applicable eligibility criteria and may be recognized when the results are announced, but they are not permitted to receive any monetary prizes. Each team must designate a captain who must be a U.S. citizen or permanent resident and who is responsible for all correspondence regarding this challenge. The official language regarding eligibility can be found on NCATS’ Challenge Details page. May federal employees participate in the challenge? Participants may NOT be a federal entities or federal employees acting within the scope of their employment. Participants may NOT be employees of HHS acting in a personal capacity. If employed by a federal agency other than HHS, participants should consult with an ethics official at their respective agencies to determine if participation violates federal ethics rules. Is an account with challenge.gov required to compete, and how do prospective participants set up such an account? Yes. Every entrant must register for the challenge, even if participating as a member of a team. Innovators can access the registration and submission platform by searching for “NCATS ASPIRE Design Challenges for Translational Innovation in Pain, Opioid Use Disorder and Overdose.” When you’re ready to submit, create your account as in indicated at https://challenge.gov/a/buzz/pages/about-us: Click “login” and select “register.” Create a challenge.gov username and password of your choice. Provide an email address to help us verify your account. Check your email for an alert from challenge.gov to verify your account and complete the process. Now, you’re ready to submit! How do prospective participants with existing challenge.gov accounts register for this challenge? To register for a NCATS ASPIRE Design Challenge, simply click the orange “Follow this Challenge” button in the upper right corner of the NCATS ASPIRE page on challenge.gov. What will be the method of payment? Prizes awarded under this competition will be paid by electronic funds transfer and may be subject to federal income taxes. HHS/NIH will comply with the Internal Revenue Service withholding and reporting requirements, where applicable. How will prizes be awarded? Prizes will be awarded directly to the team lead of the winning team, so award apportionment within a team is not applicable. All members of winning team(s) will be announced and recognized by NCATS. Winning team members will be listed on the NCATS website and promoted through various other NCATS communications. May participants fund development of submissions with federal funds? No. Participants may not fund the work to participate in this challenge using federal grants. As required by the America COMPETES Act, the challenge announcement states that “federal grantees may not use federal funds to develop their challenge submissions…” Therefore, alternative funding must be used to do the work. What are the options for participating in this challenge without using federal grants? Some ideas for alternate funding sources include using development money from the participant’s institution, starting a crowdfunding campaign, and applying for grants from non-federal organizations with similar goals and missions. May a participant’s company (a for-profit private entity) participate? Yes, provided that the private entity matches funds or provides documented in-kind contributions at a rate of not less than 50 percent of the total federally awarded amount, as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018. Winner(s) will be required to demonstrate that matching funds and/or in-kind contributions were committed to achieve the winning solution. How are entries evaluated and winners selected? All entries will be evaluated using a two-step process. First, technical consultants will independently evaluate prize competition entries and suggest rankings, which will be provided to the judges. The judges then will evaluate the submissions and consider the input from the technical consultants. Winners will be selected by the federal judges. Who are the technical advisory panelists or subject matter experts (SMEs)? The technical advisory panelists often are referred to as subject matter experts (SMEs) with cross-disciplinary expertise that will be necessary to best evaluate the submissions. Technical consultants will have direct experience in the fields of synthetic chemistry, drug discovery and development, database and/or algorithm development, and development of novel physiologically relevant biological assays. Pain, addiction and overdose experts will be included as well. The names of the technical consultants will be posted on the NCATS ASPIRE webpage upon confirmation of their participation. NCATS reserves the right to add technical consultants upon receipt of entries, if additional expertise is needed. Who are the judges? The judges will be federal employees who have extensive expertise related to the topics of the challenges, including, but not limited to, a wide spectrum of expertise along the drug discovery and development continuum, 2-D and 3-D biological assay development, stem cell biology, pain biology, bioengineering, and development of tools and technologies for data analysis. The names of the federal judges will be posted on the NCATS ASPIRE webpage upon confirmation of their participation. NCATS reserves the right to add members to the judging panels upon receipt of entries, if additional expertise is needed. May entrants participate on multiple teams? Yes. An individual may be a team lead on multiple and clearly distinct entries and/or a team member on multiple entries. May a participant submit more than one solution per challenge? If so, how distinct do the solutions need to be? Yes. NCATS will allow submission of more than one solution per challenge; however, each solution proposed must be clearly distinct and utilize innovative approaches to the challenge. Different approaches would likely require different expertise that would need to be represented on the team. May entrants respond to multiple challenge areas? Or is it best to consolidate and respond to the challenge for the overall solution that comprises two or more challenge areas (Challenge 5)? Yes. Entrants may respond to multiple (two or more) challenge areas. If an entrant’s solution integrates two or more areas in a single solution from the very beginning, Challenge 5 is a better option. Fewer teams are anticipated to compete at this level. If a participant chooses to enter a solution for Challenge 5, he/she still may compete for individual challenges. If selected, the winners should be willing to team up with other innovators to work towards an integrated solution in the follow-up Reduction-to-Practice phase. What information should be included in an entry? Please provide the team lead’s name and affiliation, names and affiliation of other team members, and indicate the name of the challenge in which you are competing. Please refer to the application template for further information. May an entrant’s biographical sketch exceed five pages? What should be included in the biographical sketch? No. The biosketch is limited to five (5) pages. The biosketch may be used in combination with the feasibility section to demonstrate that the entrant’s team has the expertise to carry out the proposed protocol. For each team member, NCATS suggests including a brief summary of expertise, any accomplishments that were directly relevant to the team members’ abilities to carry out their roles, and any other information directly relevant to a challenge the participant is entering. When should teams form, and what is NCATS’ level of involvement with the teams? NCATS expects the team formation aspect for challenges to be flexible and of maximum benefit towards addressing the challenge area (i.e., assemble your teams as needed to push the science forward). If you are proposing to incorporate ideas/technology outside your area of expertise, you and the team members with the expertise should agree to work together in advance of submitting the proposal, so that the team members and their expertise can be presented in the “feasibility” section (see the application template). Each team member must register on challenge.gov, but no announcement of the team is required prior to the submission deadline. Teams may also form, add members, divide, or merge at any point during the competition. Any agreements among participants who decide to collaborate are at the discretion of those involved. NCATS is not overseeing collaborations, and each team is responsible for its own assembly and disassembly. NCATS simply wants to maximize the flexibility for all participants, in order to have the best chance of achieving the solution. For example, if a non-winning team finds that it is not feasible to move forward without winning some seed money from the proposal, and the team disassembles, we encourage those with expertise and interest to pursue membership with other teams. Are preliminary data required for the design solutions? Preliminary data are NOT required but are allowed. Are participants required to use a particular data set? No. Data may be aggregated from available public and/or private sources, provided that participants certify that they have the proper freedom to operate, utilize and present the data in an open source format. Please provide the license and terms under which they are provided for all included datasets. May participants ask additional questions? Are program staff available to discuss scientific or technical questions by phone? Questions can be emailed to NCATSASPIREChallenge@mail.nih.gov. NCATS staff members are not available for discussions by phone or through direct emails. What are included in matching funds or in-kind contributions? Matching funds may include cash expenditures by the entrant and the value of allowable third-party in-kind contributions. Allowable in-kind contributions may include volunteer services, loaned/donated equipment, space, staff salaries, supplies, etc. In all cases, costs and contributions are subject to verification before a prize can be awarded. The source of these matching funds excludes federal grants and contracts, including SBIR/STTR grants. State or local funds, private or corporate donations can be used to meet the matching requirement. No federal funds will be considered, even if for activities related to submitting the entry, but not developing the design, to determine the amount of matching funds. Funds from other nonfederal entities or nongovernmental entities may be used. Is there a minimum amount of matching funds required to enter the competition? No. There is no minimum amount of matching funds required to enter the competition. However, the amount of the prize will be adjusted so that the prize amount reflects the amount of the matching funds documented with the submission. The amount of matching funds will not be considered in the assessment of the quality of the design. How should a prospective participating company (for-profit private entity) document the matching funds? For-profit entities should include specific information that identifies the source and amount of all funds to be considered when determining the amount of matching funds that supported development of the submitted design. In addition, submissions should also include a statement of assurance that federal funds were not used to develop the design that is being submitted for the challenge. Costs and contributions will be subject to verification before a prize can be awarded. When is documentation of matching funds required? The documentation of the contribution of matching funds is due at the time the design is submitted, not upon receipt of the prize award. Will applications to advance in vivo biological assays be considered? No. Only in vitro biological assays that are physiologically relevant and use renewable sources of human cells (such as iPSCs) will be considered. The assay must be amenable to high-throughput screening in the future. For the envisioned reduction to practice stage, will winners of the Design Challenges be required to work with each other? No. While all winners of the design challenges will be invited to participate in this stage, no teaming will be forced. As with these Design Challenges, collaboration will be highly encouraged. New teams with innovative approaches also are invited to apply. Does NCATS have a video where applicants can learn more? Yes. Applicants are encouraged to learn more from this informational applicant video. | NCATS ASPIRE Design Challenges Questions and Answers | NCATS ASPIRE Design Challenges Questions and Answers | ||||||
| 13855 | CTSA Program Support Kick-Starts Career and Emerging Research on Health Effects of Plastics | February 1, 2019For newborns or children in the pediatric intensive care unit, plastic tubing is part of daily life. It delivers life-sustaining blood transfusions, liquid nutrition and air to breathe. But small amounts of the chemicals in the plastic of this tubing and other medical devices can leak into the patient’s bloodstream. The potential effects of these chemicals on the developing hearts of newborns and very young children are not well understood.Early-stage investigator Nikki Posnack, Ph.D., an assistant professor at the Children’s National Heart Institute and Sheikh Zayed Institute for Pediatric Surgical Innovation, sought to close this knowledge gap. In 2016, she received pilot funding from the NCATS’ Clinical and Translational Science Awards (CTSA) Program hub at Children’s National Health System, kick-starting an emerging area of research — and her career.“While plastics have revolutionized the medical field, we know chemicals in plastics leach into the body and may have unintended effects,” Posnack said. “The heart is sensitive to toxins, so we want to look at the effect of these plastics on the most sensitive patient population: kids who are recovering from heart surgery and already prone to cardiac complications.”A Question Leads to a CareerNikki Posnack, Ph.D., guides research to explore how chemicals used in medical devices and consumer products may alter heart function. (Children’s National Health System Photo)Several years ago, Posnack was completing graduate research training on a team studying the heart’s electrical activity when she was approached by a toxicologist from the U.S. Food and Drug Administration. He wanted to know if the chemical DEHP, found in flexible medical devices such as plastic tubing, could affect heart function. Chemicals like DEHP are known to affect the body’s hormones and have been removed from many consumer products. But they remain in certain medical devices because they have properties needed for the devices and safer alternatives have not been extensively tested.In the laboratory, Posnack began looking at the effects on heart cells of DEHP and other chemicals found in plastics. These early studies suggested that the chemicals could affect the cells’ electrical activity, especially over long periods of exposure.What began as a collaboration would go on to become the focus of Posnack’s research as she started her own lab. After joining Children’s National in 2016, Posnack recognized that she would need new skills and methods to get to the bottom of this unanswered question.Carving a Path as an Early-Stage InvestigatorPosnack applied for CTSA Program pilot funding to adopt several critical techniques in her lab. One addressed how to determine the amount of chemicals from plastics that were leaking into a patient’s bloodstream. In collaboration with two nearby labs specializing in the technique of mass spectrometry, she honed the method using blood and urine samples from rats.Mass spectrometry, which measures the mass of different molecules within a sample, enabled Posnack to see how much of the chemicals reached the rats’ hearts. This led to her first study in animal models. The results, published in the Nov. 6, 2017, issue of the American Journal of Physiology, showed that exposure to DEHP affected the nervous system’s ability to control heart rate following stress in adult rats. Moreover, the study was the first to show a link between chemicals called phthalates — one of which is DEHP — and heart toxicity in an animal model.Posnack predicted that the developing heart of a newborn might be even more sensitive to the effects of chemicals from plastics. Using heart cells from newborn mice, grown in the lab, she examined the effects of another chemical, bisphenol A (BPA), which can also be found in plastic medical devices. BPA had substantial effects on the developing heart cells, leading to slower heart rates, irregular heart rhythms and skipped beats. That study, published in the May 9, 2018, issue of Scientific Reports, was the first to look at how BPA exposure affects heart cells that are still developing.“People have known that BPA can have negative consequences on human health, but this research shows its effects may be much more extensive and could impact the hearts of young patients,” said Michael G. Kurilla, M.D., Ph.D., director of the NCATS Division of Clinical Innovation, which includes the CTSA Program. “Posnack is pioneering this emerging area of research that has significant public health implications.”Toward a Better Translational ModelAlthough animal models provide evidence that a chemical might be toxic, there are differences — especially in the developing heart — that may limit the translation of findings from animal models to humans. To address this obstacle, Posnack wanted to develop a better model for young human heart cells. First, she had to learn how to work with induced pluripotent stem cells (iPSCs). These special cells, created in the lab from adult human skin or blood cells, can be coaxed into any kind of cell, including heart cells.Human heart muscle cells, created from induced pluripotent stem cells, plated on a device to measure electrical activity. (Nikki Posnack Photo)With the CTSA Program funding, Posnack sent a postdoctoral researcher to a collaborator’s lab to learn how to grow iPSCs and turn them into heart cells. She has since honed this technique in her lab and is developing a better model for looking at toxicity in the pediatric heart.With this new skill and the ability to measure chemical exposure in patients, Posnack was awarded her first R01 grant, a five-year award from the National Heart, Lung, and Blood Institute, in 2018. The R01 is considered to mark the transition from an early-stage researcher to an independent investigator. Helping scientists navigate this career transition is a key CTSA Program goal.“The CTSA Program funding provided the preliminary data that showed we could actually do the research to answer these critical questions and it wasn’t just a pipedream,” Posnack said.Building the Evidence BasePosnack is beginning to use her iPSC-derived heart model to screen chemicals from plastics currently in use in medical devices as well as alternatives that have recently come on the market. With independent funding and the techniques developed through the CTSA Program pilot project, she also has been collecting samples and vital sign data from pediatric patients who undergo medical procedures at Children’s National. This information will enable her to link high or low exposure levels with different outcomes, such as heart rate or blood pressure variability, which will help translate results from her iPSC model to humans.“These chemicals are still used in so many medical devices,” Posnack said. “I think people are becoming aware of the negative effects of certain chemicals, and they will eventually be phased out. But it will require additional data to determine if these chemicals can be harmful to kids.” | An early-career investigator has developed techniques to study how chemicals used in medical devices affect the still-developing hearts of pediatric patients. | /sites/default/files/Nikki-Posnack_1260x630.jpg | CTSA Program Supports Emerging Research on Health Effects of Plastics | An early-career investigator has developed techniques to study how chemicals used in medical devices affect the still-developing hearts of pediatric patients. | /sites/default/files/Nikki-Posnack_1260x630.jpg | CTSA Program Supports Emerging Research on Health Effects of Plastics |
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