Posts tagged with "UVA"

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Scientists Mapping Next Pandemic

An international team of scientists has created a powerful new resource to speed the development of vaccines and treatments to battle the next pandemic.

University of Virginia School of Medicine researcher Wladek Minor, PhD, and collaborators in China and Poland have developed an Internet information system, called virusMED, that lays out all we know about the atomic structure and potential vulnerabilities of more than 800 virus strains from 75 different virus families, including SARS-CoV-2, influenza, Ebola and HIV‑1. Several of the collaborators, including the lead investigator, Heping Zheng, are former students and members of Minor’s lab at UVA. 

This new panorama of the proteins of potential threats will help scientists respond quickly and effectively against the next pathogen poised to wreak havoc on humanity. Minor and his collaborators compare the resource to Google Maps, in that it organizes and annotates major points of interest on a virus that scientists can use as a roadmap in drug and vaccine development.

“The battle with COVID-19 is not over yet, but we cannot wait to start preparing for the next pandemic. VirusMED is a step towards an advanced information system that brings together researchers with diverse expertise to tackle complex biomedical challenges,” said Minor, the Harrison Distinguished Professor of Molecular Physiology and Biological Physics at UVA. “The information contained in virusMED will help viral researchers from many disciplines, especially those working on drug design or anti-viral therapies. We provide novel structural analysis and integrate pertinent information from various resources to provide a comprehensive picture of the proteins’ most important and vulnerable regions.”

Virus Hotspots

By quickly unlocking the SARS-CoV-2 virus mechanism of action, scientists were able to develop safe and effective vaccines for COVID-19. Minor’s new database aims to put that type of critical information at scientists’ fingertips in one convenient location.

VirusMED contains extensive information on virus species and strains, hosts, viral proteins and antibodies, as well as drugs that have already been approved by the U.S. Food and Drug Administration, among other important scientific data. The researchers call the points of interest on a virus its “hotspots,” and these hotspots make for strong starting points for drug and vaccine development.

“One of the most promising strain-indifferent antibody therapies developed for the treatment of COVID-19 used this type of information to improve upon a unique antibody isolated from a survivor who was infected by the SARS virus back in 2003,” said David Cooper, PhD, research faculty in Minor’s lab. “People who are surprised by rapid drug and vaccine design don’t realize that researchers today are building upon decades of previous research.”

One of virusMED’s major advantages is that it brings together the extant knowledge about viruses in one location, Minor said. Previously, that data was spread across multiple resources and often “siloed” so that it was not easily accessible. With virusMED, researchers can browse the information by virus or by their hotspot of interest.

The free and accessible database can be found HERE.

“One of the goals of my lab is to make tools that other scientists can use. We look at the forest and find ways to help others focus on the trees,” Minor said. “Resource generation is not glamorous, but the ultimate goal of science is to make life better. One of the anonymous peer-reviewers of the paper claimed they instantly became an enthusiastic user of the system. We expect virusMED to really make a difference.”

Findings Published

The researchers have published their findings in the scientific IUCr Journal. The work will be featured on the journal’s cover. The research team consisted of HuiHui Zhang, Pei Chen, Haojie Ma, Magdalena Woinska, Dejian Liu, Cooper, Guo Peng, Yousong Peng, Lei Deng, Minor and Zheng. .

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

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Osteoporosis: New Approach to Understanding Bone Strength

Innovative Research Reveals Genes That Influence Osteoporosis

 

Researchers at the University of Virginia School of Medicine have taken a new approach to understanding how our genes determine the strength of our bones, allowing them to identify several genes not previously known to influence bone density and, ultimately, our risk of fracture.

 

The work offers important insights into osteoporosis, a condition that affects 10 million Americans, and it provides scientists potential new targets in their battle against the brittle-bone disease.

 

Importantly, the approach uses a newly created population of laboratory mice that allows researchers to identify relevant genes and overcome limitations of human studies. Identifying such genes has been very difficult but is key to using genetic discoveries to improve bone health.

 

“Genome-wide association studies have revolutionized the identification of regions of the human genome that influence bone mineral density. However, there are challenges to using this information to help patients, such as identifying the specific genes involved. Additionally, such studies have focused only on bone mineral density, although many other aspects of bone contribute to bone strength and risk of fracture but cannot be measured in humans,” said Charles Farber, PhD, of UVA’s Center for Public Health Genomics and Department of Public Health Sciences. “The ability to use mice in a novel way has allowed us to begin to overcome the challenges associated with human genome-wide association studies.”

 

Understanding Osteoporosis and Bone Strength

 

Genome-wide association studies have identified more than 1,000 locations on our chromosomes where genes are found that influence bone mineral density (BMD), a strong predictor of how likely an individual is to experience a bone fracture. But bone mineral density is only one factor in bone strength. Farber and his colleagues wanted to get a more complete picture.

 

They created a resource by collecting information on 55 different skeletal characteristics in hundreds of mice and then used an approach called systems genetics to analyze the data. The analysis identified a total of 66 genes that contribute to BMD, including 19 not previously linked to BMD.

 

Of the 19, the researchers were able to determine that two, SERTAD4 and GLT8D2, likely affect bone mineral density through cells that form bone called osteoblasts. This ability to determine the cell types that genes use to perform biological processes is one of the great strengths of systems genetics analysis, the researchers say.

 

The scientists also found that another gene, QSOX1, plays an important role in determining the mass and strength of the outer, “cortical” layer of bone. This type of bone makes up 80% of our skeleton and is vital for bone strength and weight-bearing.

 

In addition to providing new insights into osteoporosis, the new findings highlight the tremendous potential of using mice to identify important genes in humans, Farber says.

 

“The information we generated from mice can be used in the future to evaluate these newly identified genes as potential drug targets,” said Basel Al-Barghouthi, of UVA’s Center for Public Health Genomics, who led the analysis. “Furthermore, these approaches can be applied across a wide range of diseases.”

 

Findings Published

 

The researchers have published their findings in the scientific journal Nature Communications. The research team consisted of Al-Barghouthi, Larry D. Mesner, Gina M. Calabrese, Daniel Brooks, Steven M. Tommasini, Mary L. Bouxsein, Mark C. Horowitz, Clifford J. Rosen, Kevin Nguyen, Samuel Haddox, Emily A. Farber, Suna Onengut-Gumuscu, Daniel Pomp and Farber.

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COVID-19 Wastewater Testing

COVID-19 Wastewater Testing Proves Effective in New Study, Research Offers Needed Guidance for Early Detection in Nursing Homes, Dorms

Wastewater testing is an effective way to identify new cases of COVID-19 in nursing homes and other congregate living settings, and it may be particularly useful for preventing outbreaks in college dormitories, a new University of Virginia study finds.

The research, a collaboration of UVA’s School of Medicine and School of Engineering, was led by UVA Health’s Amy Mathers, MD. It offers some of the first clear guidance on the most effective methods to perform testing to detect COVID-19 in wastewater.

The researchers evaluated and compared sampling and analysis techniques by testing them within buildings with known numbers of positive cases. They were then able to determine wastewater testing’s strengths and limitations as a tool for monitoring COVID-19 in a building population. For example, the technique proved better at detecting initial infections than determining the number of occupants infected or how long they had been infected. 

One important answer revealed by the research: Wastewater testing can detect even small numbers of asymptomatic cases, something not previously documented.

“This work could be applied to surveillance in buildings where people live in groups, where transmission may be hard to control but the risk of spread could be high,” said Mathers, an infectious disease expert in the School of Medicine’s Department of Pathology. “Since we can identify new infections with high sensitivity, it provides an early warning signal of when to test everyone in the building to find and isolate the newly infected persons before an outbreak becomes large.”

Wastewater Testing for COVID-19

To evaluate the effectiveness of wastewater testing for detecting COVID-19, Mathers collaborated with Lisa Colosi-Peterson, PhD, an associate professor in UVA Engineering’s Department of Engineering Systems and Environment, who connected with Mathers through UVA’s Center for Engineering in Medicine. They and their colleagues monitored wastewater from two student dormitory complexes for eight weeks. They then compared their findings to the results of periodic student testing UVA had implemented to prevent COVID-19 transmission. The researchers found that the wastewater testing caught more than 96% of cases.

One limitation of wastewater testing: It could not distinguish between new infections and virus found in stool from those who had recovered and were no longer contagious. That means the wastewater testing detected both active and former cases. “The inability to distinguish recently infected but no longer contagious persons from new contagious infections within a building is an important finding, as it means that wastewater testing would be best for identifying new cases and isolating individuals in groups without recent infections,” Mathers said.

UVA’s new research also establishes useful protocols for wastewater testing. In a scientific paper outlining their findings, the researchers describe how they collected and tested the samples, noting that refrigerating the samples on ice adequately preserved them for testing that same day. Institutions that plan to send their samples elsewhere for testing, however, may need to take additional steps to preserve the samples for longer, the researchers note. Cleansers and disinfectants used in the facilities could also degrade the viral RNA over time, they caution.

While the researchers are urging further study, they conclude that wastewater testing holds great promise for detecting and controlling COVID-19 in places where people live in close quarters. “Passive pooled surveillance of wastewater is now serving as an early warning system in many dormitories, barracks and prisons to identify new cases in situations where transmission risk is high,” Mathers said. “Applications for wastewater surveillance to inform and control infectious disease transmission will continue to evolve, but it is hard to believe how far and how fast we have come in the last year.”

Findings Published

The project was a collaborative effort of UVA’s School of Medicine, School of Engineering, School of Data Science and UVA Health’s Facilities Management. The research team consisted of Colosi-Peterson, Katie E. Barry, Shireen M. Kotay, Michael D. Porter, Melinda D. Poulter, Cameron Ratliff, William Simmons, Limor I. Steinberg, D. Derek Wilson, Rena Morse, Paul Zmick and Mathers.

The researchers have published their findings in the scientific journal Applied and Environmental Microbiology.

The work was supported by a UVA Engineering in Medicine Seed Grant and support from the University Reopening Committee.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

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Cold Sore Flareup Triggers

Virus Highjacks Important Immune Response, UVA Discovery Reveals

Researchers at the University of Virginia School of Medicine have shed light on what causes herpes simplex virus to flare up, explaining how stress, illness and even sunburn can trigger unwanted outbreaks.

The discovery could lead to new ways to prevent cold sores and recurrent herpes-related eye disease from reoccurring, the researchers report.

“Herpes simplex recurrence has long been associated with stress, fever and sunburn,” said researcher Anna R. Cliffe, PhD, of UVA’s Department of Microbiology, Immunology and Cancer Biology. “This study sheds light on how all these triggers can lead to herpes simplex-associated disease.”

About Herpes Simplex Recurrence

Once you’re infected with herpes simplex virus (HSV) – and more half of Americans are – the virus never really goes away. Instead, it lurks inside neurons, waiting for the right moment to strike again, a process known as reactivation.

Cold sores, also known as fever blisters, are one of the most common symptoms of HSV reactivation. Recurrent reactivation in the eye leads to herpes keratitis, which, if left untreated, can result in blindness. HSV infection has also been linked to the progression of Alzheimer’s disease.

Recurrences of HSV are typically associated with stress, illness or sunburn, but doctors have been uncertain exactly what causes the virus to reactivate. Cliffe and her collaborators found that when neurons harboring the virus were exposed to stimuli that induce “neuronal hyperexcitation,” the virus senses this particular change and seizes its opportunity to reactivate.

Working in a model developed by the Cliffe lab using mouse neurons infected with HSV, the researchers determined that the virus highjacks an important immune response within the body. In response to prolonged periods of inflammation or stress, the immune system releases a particular cytokine, Interleukin 1 beta. This cytokine is also present in epithelial cells in the skin and eye and is released when these cells are damaged by ultraviolet light.

Interleukin 1 beta then increases the excitability in the affected neurons, setting the stage for HSV to flare up, the UVA researchers discovered.

“It is really remarkable that the virus has hijacked this pathway that is part of our body’s immune response,” Cliffe said. “it highlights how some viruses have evolved to take advantage of what should be part of our infection-fighting machinery.”

The scientists say that more research will need to be done to fully understand the potential factors which play into herpes simplex disease. It may vary depending on the virus strain or the type of neuron infected, even. And it is still unknown if the virus alters how neurons respond to cytokines such as Interleukin 1 beta. But the new insights help doctors better understand what is happening in neurons and the immune system, and that could lead to ways to prevent unwanted outbreaks, the researchers hope.

“A better understanding of what causes HSV to reactivate in response to a stimulus is needed to develop novel therapeutics,” Cliffe said. “Ultimately, what we hope to do is target the latent virus itself and make it unresponsive to stimuli such as Interleukin 1 beta.”

Findings Published

The researchers have published their findings in the scientific journal eLife. The research team consisted of Sean R. Cuddy, Austin R. Schinlever, Sara Dochnal, Philip V. Seegren, Jon Suzich, Parijat Kundu, Taylor K. Downs, Mina Farah, Bimal N. Desai, Chris Boutell and Cliffe.

The work was supported by the National Institutes of Health’s National Institute of Neurological Disorder and Stroke, grant R01NS105630; the National Institute of Allergy and Infectious Diseases, grant T32AI007046; the National Eye Institute, grant F30EY030397; the National Institute of General Medical Sciences, grants T32GM008136, T32GM007267, GM108989 and GM007055and Medical Research Council grant MC_UU_12014/5.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

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Antibody Cocktail May Prevent Symptomatic COVID-19 Infections

An antibody cocktail being tested at UVA Health and other sites was able to block 100% of symptomatic COVID-19 infections among people exposed to the virus, early results from the clinical trial suggest.

In addition, those who developed asymptomatic infections accumulated far less virus in their bodies than usual and saw their infections resolve within a week, according to interim data released by the cocktail’s manufacturer, Regeneron Pharmaceuticals.

“This is the first treatment shown to prevent COVID-19 after a known exposure, and offers protection for unvaccinated individuals caring for a family member with COVID-19,” said UVA Health’s William Petri Jr., MD, PhD, one of the leaders of the trial at UVA. “We expect that Regeneron will file for Emergency Use Authorization from the FDA so that this drug can be used outside of the context of a clinical trial.”

Antibodies for COVID-19

The phase 3 clinical trial aims to determine if the antibodies will prevent COVID-19 infection in people who have been exposed but not yet developed the disease. This is known as “passive immunization.”

Regeneron’s new analysis, which has not yet been published in a scientific journal, looked at outcomes in approximately 400 trial participants. Of 186 people who received the antibodies, none developed symptomatic COVID-19. Of the 223 who received a placebo, eight developed symptomatic COVID-19, the company reports.

Asymptomatic infections occurred in 15 of the antibody recipients and in 23 of the placebo recipients. Overall rates of infection, including both symptomatic and asymptomatic infections, were approximately 50% lower in the antibody group.

Among those who developed infections, placebo recipients had, on average, a peak viral load (the amount of virus in the body) that was more than 100 times greater than antibody recipients. The antibody group also recovered more quickly–all the infections resolved within seven days, while 40 percent of infections in the placebo group lasted three to four weeks, Regeneron said.

The cocktail also appears to shorten the duration of viral shedding, the time when the virus is being manufactured in the body. The viral shedding period was nine weeks among antibody recipients and 44 weeks among the placebo recipients. While people with COVID-19 are not infectious for this entire time, reducing the duration of viral shedding may shorten the period when they can spread the disease.

There were more adverse events reported among placebo recipients than among antibody recipients – 18 percent and 12 percent, respectively. Regeneron attributed this to the larger number of COVID-19 infections in the placebo group.

There was one death and one COVID-19-related hospitalization in the placebo group and none in the antibody group. Injection-site reactions were reported among 2 percent of both groups.

“We are profoundly grateful to the nurses and staff of the UVA COVID-19 clinic, led by Dr. Debbie-Anne Shirley,” Petri said. “Their day-to-day support made our participation in this trial possible.”

About the Clinical Trial

Phase 3 clinical trials, such as the one under way at UVA, examine the safety and effectiveness of new drugs and treatments in large numbers of people. Positive results in the phase 3 trial could spur the federal Food and Drug Administration to make the antibody cocktail available for post-exposure COVID-19 prevention.

The antibody cocktail is not a vaccine and is not expected to provide permanent immunity to COVID-19.

The team conducting the study at UVA is led by Petri and Shirley and includes Gregory Madden, MD; Chelsea Marie, PhD; Jennifer Sasson, MD; Jae Shin, MD; Cirle Warren, MD; Clinical Research Coordinator Igor Shumilin; assistant Rebecca Carpenter; and COVID-19 Clinic nurses Michelle Sutton, Elizabeth Brooks, Danielle Donigan, Cynthia Edwards, Jennifer Pinnata, Samantha Simmons and Rebecca Wade.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

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UVA’s DNA Discovery

Scientists have identified a group of drugs that may help stop a leading cause of vision loss after making an unexpected discovery that overturns a fundamental belief about DNA.

The drugs, known as Nucleoside Reverse Transcriptase Inhibitors, or NRTIs, are commonly used to treat HIV. The new discovery suggests that they may be useful against dry macular degeneration as well, even though a virus does not cause that sight-stealing condition.

A review of four different health insurance databases suggests that people taking these drugs have a significantly reduced risk of developing dry macular degeneration, a condition that affects millions of Americans.

“We are extremely excited that the reduced risk was reproduced in all the databases, each with millions of patients,” said Jayakrishna Ambati, MD, a top macular degeneration researcher at the University of Virginia School of Medicine. “This finding provides real hope in developing the first treatment for this blinding disease.”

Targeting Macular Degeneration

The new discovery comes from Ambati; Fred H. Gage, PhD, of the Salk Institute for Biological Studies; and collaborators around the world. The work rewrites our understanding of DNA, revealing for the first time that it can be manufactured in the cytoplasm of our cells, outside the cell nucleus that is home to our genetic material.

The buildup of a certain type of DNA in the cytoplasm, Alu, contributes to macular degeneration, the researchers found. This buildup appears to kill off an important layer of cells that nourishes the retina’s visual cells.

Based on this discovery, the researchers decided to look at drugs that block the production of this DNA, to see if they might help prevent vision loss. They analyzed multiple U.S. health insurance databases – encompassing more than 100 million patients over two decades – and found that people taking NRTIs were almost 40% less likely to develop dry macular degeneration.

The researchers are urging further study to determine if these drugs or safer derivatives known as Kamuvudines, both of which block a key inflammatory pathway, could help prevent vision loss from dry macular degeneration.

“A clinical trial of these inflammasome-inhibiting drugs is now warranted,” said Ambati, the founding director of UVA’s Center for Advanced Vision Science. “It’s also fascinating how uncovering the intricate biology of genetics and combining it with big data archeology can propel insights into new medicines.”

Ambati, of UVA’s Department of Ophthalmology, previously determined that NRTIs may help prevent diabetes as well.

Findings Published

The researchers have published their findings in the scientific journal PNAS. The research team consisted of Shinichi Fukuda, Akhil Varshney, Benjamin J. Fowler, Shao-bin Wang, Siddharth Narendran, Kameshwari Ambati, Tetsuhiro Yasuma, Joseph Magagnoli, Hannah Leung, Shuichiro Hirahara, Yosuke Nagasaka, Reo Yasuma, Ivana Apicella, Felipe Pereira, Ryan D. Makin, Eamonn Magner, Xinan Liu, Jian Sun, Mo Wang, Kirstie Baker, Kenneth M. Marion, Xiwen Huang, Elmira Baghdasaryan, Meenakshi Ambati, Vidya L. Ambati, Akshat Pandey, Lekha Pandya, Tammy Cummings, Daipayan Banerjee, Peirong Huang, Praveen Yerramothu, Genrich V. Tolstonog, Ulrike Held, Jennifer A. Erwin, Apua C.M. Paquola, Joseph R. Herdy, Yuichiro Ogura, Hiroko Terasaki, Tetsuro Oshika, Shaban Darwish, Ramendra K. Singh, Saghar Mozaffari, Deepak Bhattarai, Kyung Bo Kim, James W. Hardin, Charles L. Bennett, David R. Hinton, Timothy E. Hanson, Christian Röver, Keykavous Parang, Nagaraj Kerur, Jinze Liu, Brian C. Werner, S. Scott Sutton, Srinivas R. Sadda, Gerald G. Schumann, Bradley D. Gelfand, Fred H. Gage and Jayakrishna Ambati.

Jayakrishna Ambati is a co-founder of Inflammasome Therapeutics, iVeena Holdings, iVeena Delivery Systems and DiceRx; a full list of the authors’ disclosures is included in the paper.

The research was supported by UVA’s Strategic Investment Fund, the National Institutes of Health Director’s Pioneer Award, the National Institutes of Health’s National Eye Institute and many other generous contributors. A full list is included in the paper.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

Science Tech Illustration by Gabrielle Archuleta

Blood Discovery Research x UVA

Blood Discoveries Advance Effort to Grow Organs, Battle Cancer 

New Research Reveals Important Insights Into How Our Bodies Make Blood 

CHARLOTTESVILLE, V.A.– Pioneering research into how our bodies manufacture the cells that make blood has moved us closer to regrowing tissues and organs. These findings also may let doctors grow the cells for transplantation into people to battle cancer, blood disorders and autoimmune diseases.

Researcher Karen K. Hirschi, PhD, of the Department of Cell Biology and Cardiovascular Research Center at the University of Virginia School of Medicine, has developed a simple and efficient way to generate “hemogenic endothelial cells.” These cells are the first step in the production line of blood cells, and Hirschi’s new findings provide a blueprint for creating them outside of the body.

“By studying how hemogenic endothelial cells develop normally, we gain the insight needed to generate them in the lab,” Hirschi said. “Now that we have established a method to produce human hemogenic endothelial cells outside of the body, we will continue to improve their production and function as we learn more about the mechanisms that promote their normal development.”

Building Blood-Making Factories

Hirschi’s latest work, published in a pair of scientific papers, offers important insights into how hemogenic endothelial cells form, and how they ultimately give rise to the cells that directly manufacture blood.

Writing in the prestigious journal, Science, she and her team reveal a key trigger that causes the endothelial cells to “transdifferentiate,” or turn into blood-making factories, during embryonic development. These blood-making (i.e. hemogenic) endothelial cells generate hematopoietic stem and progenitor cells (HSPCs) that have long been used for the treatment of cancer and other diseases. Typically, they are taken from sources such as an individual’s bone marrow, but doctors would like to be able to manufacture them quickly and easily for patients on demand. “Generating human hemogenic endothelial cells in the lab from each patient that needs HSPC is the first step toward patient therapies for blood disorders,” Hirschi said.

In a paper published nearly simultaneously in Cell Reports, Hirschi unveils a blueprint for creating the hemogenic endothelial cells, the source of HSPCs, outside of the body. The secret is a substance called retinoic acid. You may have heard of retinoic acid in association with beauty products, but in this case its responsibilities include triggering genes to cause “hematopoietic transition”–to put more vascular endothelial cells in the business of making blood by producing HSPCs.

The new insights provided by the work “will improve our ability to apply developmental insights to the generation of distinct endothelial cell subtypes for tissue engineering and regenerative medicine,” the researchers write in their new paper. “In addition, our system could likely be developed further to optimize the generation of transplantable HSPCs from human hemogenic endothelial cells for clinical therapies.”

The approach offers several advances over existing means, including being quicker and less expensive, the researchers note.

“We hope our continued efforts will move us closer to treating both vascular and blood disorders,” Hirschi said. “These studies highlight the importance of basic cell and developmental biology research as a foundation for devising strategies for patient-specific clinical therapies.”

Hirschi was recruited from Yale in 2019 to join the faculty in the Department of Cell Biology, which has long been interested in addressing how embryos develop and applying this basic knowledge to the repair and regeneration of damaged tissues and organs.

Findings Published

The Science paper was authored by Dionna M. Kasper, Jared Hintzen, Yinyu Wu, Joey J. Ghersi, Hanna K. Mandl, Kevin E. Salinas, William Armero, Zhiheng He, Ying Sheng, Yixuan Xie, Daniel W. Heindel, Eon Joo Park, William C. Sessa, Lara K. Mahal, Carlito Lebrilla, Hirschi and Stefania Nicoli. The work was supported by the National Institutes of Health (grants F32HL132475, U54DK106857, 1K99HL141687, R01HL130246, R56DK118728, R01HL146056. R01HL128064, R01DK118728 and R01GM049077) and the American Heart Association (grants 19PRE34380749 and19TPA34890046).

The research team responsible for the Cell Reports paper consisted of Jingyao Qiu, Sofia Nordling, Hema H. Vasavada, Eugene C. Butcher and Hirschi. That work was supported by NIH grants HL128064, U2EB017103, R01-AI130471 and R01-CA228019; CT Innovations grant 15-RMB-YALE-04; Department of Veterans Affairs Merit Review award I01BX002919; the Swedish Society for Medical Research; and a Stanford Dean’s Fellowship.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

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UVA Tests Different Approach to Managing Type 2 Diabetes

A researcher at the University of Virginia School of Medicine is testing what he calls a “radically different” approach to managing type 2 diabetes for those who can’t or don’t want to lose weight.

Daniel Cox, PhD, professor of psychiatry and internal medicine, said his program “flies in the face of conventionality” in that it doesn’t insist on weight loss as a key component of controlling blood sugar. Instead, it combines continuous glucose monitoring with well-informed eating choices, to understand the effect of different foods on blood-sugar levels, and well-timed exercise, to reduce those levels as needed.

“The convention is ‘lose weight.’ And if you lose weight, you lose belly fat, and if you lose belly fat, you lose adipose tissue in the liver. And that, in turn, reduces insulin resistance,” Cox said. “That’s all fine and good. And if you can, in fact, lose a significant amount of weight and keep it off for a long time – a lifetime – you’re golden. You can even put diabetes in remission. There’s nothing wrong with that approach, and it’s a very effective approach. But some people don’t need to lose weight, and some people don’t want to lose weight, and other people want to lose weight but they can’t, or they can’t keep it off for a lifetime.”

A Different Take on Diabetes Management

Cox’s approach relies on continuous glucose monitoring to help people understand how their food choices affect their blood sugar. Different foods may affect people differently, he notes.medicine

Continuous glucose monitoring involves wearing a sensor on the back of the arm that continually sends a signal to a receiver that shows the person’s blood glucose level, without the need for fingersticks. Continuous glucose monitoring lets people see how a particular food affects their blood-glucose levels, whether it’s a sugary slice of cake or a seemingly healthy bowl of oatmeal, Cox said. Understanding that lets them make smart choices to keep their blood sugar under control.

If they do choose to indulge in a sugar-spiking food, the program encourages them to use light exercise, such as walking, to help bring their blood sugar back into check.

“This is the innovation: One, you dampen how much [blood sugar] goes up by minimizing the amount of carbohydrate you eat, and, two, you hasten its recovery by becoming more physically active,” Cox said. “Physical activity does two things: One, the skeletal muscle burns blood glucose as fuel, and, two, physical activity reduces your insulin resistance for a short period of time, about 24 hours.”

“Instead of fixing supper and having a great dinner and then plopping in front of the TV for the rest of the night, the alternative is becoming more physically active,” Cox said. “Do your shopping after you eat, walk the dog after you eat, clean your house after you eat.”

About the Diabetes Clinical Trial

Cox, of UVA’s Department of Psychiatry and Neurobehavioral Sciences, is testing his approach in small clinical trials at UVA, West Virginia University and the University of Colorado. Each site is recruiting four people newly diagnosed with type 2 diabetes who have not yet begun taking medication. The participants will be provided with a treatment manual, continuous glucose monitors and activity/sleep trackers. Trial organizers will then check in with them virtually over several weeks to see how well the approach keeps their blood sugar under control.

The study is the latest in a series evaluating the approach. Cox said he has been encouraged by previous results but notes that “there’s no one approach that works for everybody.”

“In our 12-month follow-up study, slightly over half of participants – 52 percent of people – we would still classify as responders, meaning they’re having a significant benefit,” he said.

For the right people, he said, the approach may offer a way to control blood sugar without medication or with less medication, while still allowing flexibility in dietary choices. “We’re not asking for radical changes in lifestyle,” he said. “We’re asking for modest changes in lifestyle that directly impact blood sugar.”

For More Information

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

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UVA on Battling Diseases by Exercise

A top exercise researcher and colleagues at the University of Virginia School of Medicine have launched an ambitious effort to understand the whole-body benefits of exercise so that doctors can use that information to prevent and treat disease.

Zhen Yan, PhD, and his collaborators aim to identify the sources, functions and targets of the molecules that provide exercise’s well-documented health benefits. By understanding this, doctors will better understand how exercise helps fend off disease, and they may be able to design drugs to mimic those benefits for people who cannot exercise, such as those with limited mobility. The cutting-edge research could open new doors both for preventing and treating many common illnesses, the researchers hope.

“No one would dispute that physical activity or regular exercise is the best measures for health promotion and disease prevention,” said Yan, director of the Center for Skeletal Muscle Research at UVA’s Robert M. Berne Cardiovascular Research Center. “In fact, the health benefits of exercise are way beyond our imagination. The underlying reasons for the superb health benefits of exercise are being uncovered by many talented and passionate scientists around the world.”

Understanding How Exercise Improves Health

The UVA researchers have recently joined a national consortium seeking to create a “molecular map” of exercise benefits. Known as the Molecular Transducers of Physical Activity Consortium, or MoTrPAC, the group includes researchers at top institutions across the country, including Harvard, Duke, Stanford and Mayo Clinic.

The consortium came about after the National Institutes of Health invited Yan and a dozen other prominent scientists to a roundtable discussion in 2010 about the future of exercise research and the obstacles that stood in its way. The NIH then set aside almost $170 million for MoTrPAC’s research – believed to be the agency’s largest-ever investment into the mechanisms of how physical activity improves health and prevents disease.

“The program’s goal,” Yan explained, “is to study the molecular changes that occur during and after exercise and ultimately to advance the understanding of how physical activity improves and preserves health.”

The consortium is looking at exercise benefits in both humans and animal models. Initial animal research was conducted at Harvard, the University of Iowa and the University of Florida. In the latest round, UVA is joined by the University of Missouri, the University of Kansas Medical Center and the University of California, Los Angeles.

The vast amount of information collected as part of the project so far has poised the UVA team to make “unprecedented” advances, Yan reports. He and his multi-disciplinary team will employ advanced computer algorithms to sift through the heaps of data to identify specific molecules to study. They will then conduct state-of-the-art research in lab mice using gene editing, combined with a wide range of functional assessment, including muscle, cardiac, metabolic and cognitive/mental functions. This will let them determine the effects the molecules have and lay a foundation for doctors to harness the molecules to benefit human health in the future.

Yan’s team will work closely with colleagues at Stanford, who will conduct advanced “multiomics” analyses, meaning they will bring together data on genes, cellular proteins and much more to obtain a more holistic understanding of exercise’s benefits to the body.

UVA’s research team includes Yan, of the Robert M. Berne Cardiovascular Research Center and the Departments of Medicine, Pharmacology and Molecular Physiology and Biological Physics; Wenhao Xu, PhD, of the Department of Microbiology, Immunology and Cancer Biology; Chongzhi Zang, PhD, of UVA’s Center for Public Health Genomics, the Department of Public Health Sciences and the Department of Biochemistry and Molecular Genetics; Matthew Wolf, MD, PhD, of the Department of Medicine’s Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center; Thurl Harris, PhD, of the Department of Pharmacology; and Alban Gaultier, PhD, and John Lukens, PhD, both part of UVA’s Department of Neuroscience and the Center for Brain Immunology and Glia (BIG).

“It is well known that exercise is one of the best treatments for mood disorders,” Gaultier said. “We are excited to test the group discoveries using animal models of anxiety and depression.”

“This is an exciting opportunity for team science,” Zang said. “I am happy to work with colleagues at UVA and across the country and use data-science approaches to unravel the complex molecular effects of exercise.”

UVA’s effort has received almost a half-million dollars in backing from the NIH’s fund for MoTrPAC’s research.

“Our research team encompasses exceptional talents. The collective wisdom and expertise of the team at UVA and MoTrPAC will allow us to reach a level that we would not be able to reach by an individual,” Yan said. “It is an unprecedented opportunity in our lifetime to tackle this incredibly important question to mankind.”

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

MORE: Exercise may help prevent deadly COVID-19 complication.

Breast Cancer Illustration by Kaelen Felix for 360 Magazine

UVA Breast Cancer Discovery

University of Virginia Cancer Center researchers have identified a gene responsible for the spread of triple-negative breast cancer to other parts of the body – a process called metastasis – and developed a potential way to stop it.

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that accounts for 40,000 deaths in the United States annually. The majority of these deaths result from resistance to chemotherapy and subsequent aggressive metastases. So UVA researchers asked: What causes a primary tumor to become metastatic? This is an important question in cancer biology because patients with metastatic tumors have the highest death rate.

UVA’s Sanchita Bhatnagar, PhD, and her team found that the breast cancer oncogene TRIM37 not only causes the cancer to spread but also makes it resistant to chemotherapy. A new approach she and her colleagues have developed could possibly address both, the researchers hope.

“Despite metastasis being the key reason for failure of cancer therapies, it remains poorly understood. We do not clearly understand what drives the metastatic growth in patients,” said Bhatnagar, who was the first to identify TRIM37 as a breast cancer oncogene. “In general, several genes are altered during tumorigenesis. However, whether targeting the same genes will prevent metastatic transition remains to be addressed.”

Promising research from Bhatnagar’s team shows that targeting TRIM37 prevents metastatic lesions in mouse models. Those findings form the foundation of her lab’s current work exploring the role of TRIM37 in racial disparities in triple negative breast cancer. Incidence of the disease is disproportionately higher in African-American women compared with other races, with a 5-year survival rate in African-American patients of only 14% compared with 36% in non-African-American women.

Targeting Triple-Negative Breast Cancer

Bhatnagar and UVA’s Jogender Tushir-Singh, PhD, have developed a new approach to stop the effects of TRIM37 and, hopefully, prevent or significantly delay the spread of triple-negative breast cancer. This could also lower the disease’s defenses against chemotherapy.

Blocking the gene could benefit approximately 80% of triple negative breast cancer patients, the researchers estimate.

Bhatnagar and Tushir-Singh’s approach uses nanoparticles – microscopic balls of fat – to deliver treatment to block TRIM37. These nanoparticles are paired with specially engineered antibodies that bind to the cancerous cells but not to healthy cells. “As soon as the antibody finds the triple negative breast cancer cell, it binds to the receptor and is taken up by the cell,” explained Tushir-Singh, of UVA’s Department of Biochemistry and Molecular Genetics.

“It is a kiss of death,” Bhatnagar said, “that selectively reduces the expression of TRIM37 in cancer cells and prevents the spread.”

The approach could be used to deliver targeted treatments for many other cancers as well, the researchers report. “That would not only get the treatment where it needs to be but, hopefully, help prevent unwanted side effects. Besides preventing metastases, it adds selectivity,” Bhatnagar said.

“A problem in the field is, how will you give [a nanoparticle treatment] to the patients? Most of these nanoparticles are cleared by the liver, so they never have a chance to really do their job,” she said. “In this study, researchers bypassed this issue by delivering nanoparticles by nasal route, increasing the rate of uptake in the lungs – one of the most common metastatic target sites in TNBC patients.”

The development of the new approach is in its early stages, but tests with lab mice have offered encouraging indications. “The lungs showed dramatic reduction in metastatic lesions after the treatment in comparison to the mice that received no treatment,” Bhatnagar said.

Next Steps

To verify that TRIM37 targeting might offer a potential treatment approach, Bhatnagar teamed up with Tushir-Singh, her husband, to test it in the lab. “And we find that our targeted nanoparticles significantly reduce metastatic lesions in the lungs of spontaneous metastatic murine [mouse] models – both immune compromised and immune sufficient,” she said. “This is an important proof-of-concept much needed for the bench-to-clinic transition of these important findings.”

Clinically, most women in the early stages of breast cancer are treated with surgery, followed by radiation or chemotherapy. However, metastasis remains a challenging medical problem. Bhatnagar’s research offers a potential way to target a driver of metastasis that she hopes will prevent or slow metastatic progression and improve overall survival.

Much more work needs to be done, but Bhatnagar’s research is being noticed by pharmaceutical companies interested in exploring the approach’s potential. “This is a delivery platform, not only for targeting our protein of interest but for many other chemotherapeutic drugs that can be packaged into the nanoparticles and selectively delivered,” Bhatnagar said.

Findings Published

The researchers have published their findings in the scientific journal Cancer Research. The research team consisted of Piotr Przanowski, Song Lou, Rachisan Djiake Tihagam, Tanmoy Mondal, Caroline Conlan, Gururaj Shivange, Ilyas Saltani, Chandrajeet Singh, Kun Xing, Benjamin B. Morris, Marty W. Mayo, Luis Teixeira, Jacqueline Lehmann-Che, Jogender Tushir-Singh and Sanchita Bhatnagar.

Bhatnagar, a Hartwell Investigator, is supported by the Department of Defense Breast Cancer Research Breakthrough Award (BC170197P1, BC190343P1) and Metavivor Translational Research Award. A provisional patent has been filed for the molecularly targeted nanoparticle design engineered by the Bhatnagar and Tushir-Singh laboratories.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.