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Tag: University of North Carolina School of Medicine

  • UNC ObGyn, Orange County Department of Health Receive Funding to Reduce Inequities in Maternal Health Care and Outcomes

    UNC ObGyn, Orange County Department of Health Receive Funding to Reduce Inequities in Maternal Health Care and Outcomes

    Newswise — A study between the UNC Chapel-Hill and Orange County Health Department, called “Thriving Hearts: Healing-Centered, Integrated, Community Maternity Care,” has been approved for a $21-million funding award from the Patient-Centered Outcomes Research Institute (PCORI), an independent, nonprofit organization based in Washington, D.C. The funding award will be used to reduce the incidence of hypertensive disorders of pregnancy (HDP) and improve maternal outcomes across 10 North Carolina counties over the next six years.

    In the United States, rates of maternal mortality and severe maternal morbidity are rising, especially among Black and American Indian/Alaska Native women and women with disabilities, low incomes, or rural residences. Black women with HDP – a group of high blood pressure disorders that includes preeclampsia and gestational hypertension – are 3.7 times more likely to die from complications and are more likely to experience severe morbidity than their white counterparts.

    The project, led by Alison Stuebe, MD, professor of obstetrics and gynecology at the UNC School of Medicine, and Quintana Stewart, director of Orange County’s Health Department, will be coordinating with local health departments, families, and community groups to make pregnancy and birth safer. Their project strategy involves a multi-level intervention to provide support and connection at the individual patient level, the healthcare team level, and the community level.

    “The overarching goal of ‘Thriving Hearts’ is to cultivate conditions for mothers to not only survive pregnancy, but to thrive,” said Stuebe, who is also a Distinguished Scholar of Infant and Young Child Feeding at UNC Gillings School of Global Public Health. “By implementing a multi-level intervention, we want to help community advocates, health system leaders, and policymakers understand what types of support matter to growing families.”

    A Multi-Level Intervention

    The intervention will be delivered by local health departments in Alamance, Caswell, Chatham, Cumberland, Durham, Forsyth, Guilford, Johnston, Orange, and Person Counties, with the goal of strengthening the ecosystem for pregnant and parenting people across each county.

    Local health department staff will be supported to work with maternity care practices in their county to implement home blood pressure monitoring, provide healing-centered support for the health care workforce, and meet the emotional, social, and logistical needs of county residents.

    In addition to health department staff, the project team is comprised of people with lived experience of HDP, including doulas, community health workers, dieticians, social workers, nurses, and researchers. The team will be providing community-informed, multicomponent interventions that simultaneously address health conditions and social determinants of health at the individual, healthcare provider, and community level.

    At the individual level, members of the team will support prenatal clinic staff to determine patients’ risk for developing HDP. Women at high risk will receive a care kit that includes blood pressure-checking tips, a home blood pressure monitor, and a bottle of low-dose aspirin to prevent HDP. They will also be able to sign up for free informational text messages.

    Team members will also be deployed to local hospitals and clinics to provide workshops on burnout and compassion fatigue for health department staff and community healthcare providers. Along with providing small grants to neighborhood organizations, the team’s community health workers will be contacting pregnant women to introduce them to local resources and events and offering referrals to a Medical Legal Partnership to help solve problems like unsafe housing.

    The Five-Year Comparative Effectiveness Study

    Researchers will conduct a five-year study to see how well the Thriving Hearts program works. They will track the progress of the participants – about 140,000 women – before and after the Thriving Hearts program begins.

    Using hospital records, insurance claims, and birth certificates, the team will track how many women get HDP, and how well the program prevented HDP from developing. About three months after birth, the team will survey the participants about their health, well-being, and care. Healthcare workers will also be surveyed to see if their burnout lessened after their county has the Thriving Hearts program.

    Finally, the team will assess how well counties took to Thriving Hearts, and what particular elements were difficult to implement by speaking with patients, community groups, and health team members.

    The funding award for the Thriving Hearts study has been approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract.

     

    About Orange County Health Department

    The mission of Orange County Health Department (OCHD) is to promote and protect health, enhance quality of life, and preserve the environment for everyone in Orange County. In 2023, North Carolina Local Health Department Accreditation (NCLHDA) Board awarded OCHD Reaccreditation with Honors, highlighted two unique programs during their visit: Family Success Alliance (FSA), which serves families to break the cycle of poverty, and the Gateway Collaborative, which offers services in the Gateway Village housing community with the goal of bringing agencies together to support residents.

     

    About UNC School of Medicine

    The UNC School of Medicine (SOM) is the state’s largest medical school, graduating more than 180 new physicians each year. It is consistently ranked among the top medical schools in the US, including 5th overall for primary care by US News & World Report, and 6th for research among public universities. More than half of the school’s 1,700 faculty members served as principal investigators on active research awards in 2021. Two UNC SOM faculty members have earned Nobel Prize awards.

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  • Scientists Take Next Big Step in Understanding Genetics of Schizophrenia

    Scientists Take Next Big Step in Understanding Genetics of Schizophrenia

    Newswise — CHAPEL HILL, NC – Genetically speaking, we are individuals different from each other because of slight variations in our DNA sequences – so-called genetic variants – some of which have dramatic effects we can see and comprehend, from the color of our eyes to our risk for developing schizophrenia – a debilitating psychiatric condition affecting many millions worldwide. For several years, scientists have studied the entire genomes of thousands of people – called genome-wide association studies, or GWAS – to find approximately 5,000 genetic variants associated with schizophrenia.

    Now, UNC School of Medicine scientists and colleagues are figuring out which of these variants have a causal effect in the development of the schizophrenia. They are finding that some of genetic variants regulate or alter the expression of genes involved in the condition.

    Published in the journal Cell Genomics, this research marks a big step forward in our understanding of the genetic basis of schizophrenia.

     “Our findings not only provide insights into the intricate regulatory landscape of genes, but also propose a groundbreaking approach to decoding the cumulative effect of genetic variants on gene regulation in individuals with schizophrenia,” said senior author Hyejung Won, PhD, associate professor of genetics at the UNC School of Medicine. “This comprehension could potentially pave a path for more precise interventions and therapies in the future. Right now, therapeutic options are limited, and some people do not respond to drugs available.”

    For this study, Won and first authors Jessica McAfee and Sool Lee, both UNC-Chapel Hill graduate students, led a team of researchers from UCLA, Harvard, the University of Michigan, and Human Technopole in Italy to explore the genetic variants already linked to the risk of schizophrenia through GWAS research. Their goal was to figure out a way to tease apart meaningless variants from those with potential for biological activity important for developing schizophrenia. This isn’t easy for a few reasons, one of which is that genetic variants are often inherited together from parents. So, right next to each other could be two genetic variants associated with the condition – one might be important for gene expression that plays a major role in the condition, but the other variant might not have any role in the condition.

    To tackle this problem, the researchers used a special technique called a massively parallel reporter assay (MPRA) – essentially a genetic sequencing technique that can parse which variants trigger gene expression and which ones don’t. To use this method, the researchers introduced the 5,000 variants into human brain cells in a dish, cells that are essential for early brain development. These variants may or may not cause the expression of their downstream gene and genetic barcode.  The barcode, a 20bp DNA sequence, is unique to each variant. This is what the group uses to distinguish the variant sequences. The MPRA revealed 439 genetic variations with actual biological effects, meaning they can alter expression of gene.

    “Traditionally, scientists have used other epigenetic data, such as transcription factor binding and biochemically defined enhancers, to identify variants with biological effects,” Won said. “However, these conventional methods failed to predict a large portion of variants we identified to have biological effects. Our work points to a wealth of unexplored variants with biological effects.”

    To understand how these variants work together to influence gene activity, Won and colleagues developed a new model that combines data from MPRA with chromatin architecture of brain cells – that is, the genetic information important for how brain cell DNA is organized. By doing this, the researchers could connect these 439 variants to how genes are turned on or off.

    “Schizophrenia is a complex condition that is highly heritable,” Won said. “To find these 439 potentially causal variants is a big step, but we still have a lot of work ahead to figure out the complicated genetic architecture that leads an individual to develop this condition. With that information in hand, we could begin to understand the biological mechanism underlying this complex disorder, which may eventually lead to targeted therapies.”

    University of North Carolina School of Medicine

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  • New Mental Health Partnership Looks to Explain Biological Factors Behind Substance Use in Adolescents Experiencing Anxiety

    New Mental Health Partnership Looks to Explain Biological Factors Behind Substance Use in Adolescents Experiencing Anxiety

    Newswise — CHAPEL HILL, NC – Anxiety remains one of the most diagnosed clinical symptoms in adolescence and is a potent precursor to and exacerbator of substance use disorder. In their new $3.8-million study entitled “Neurobiological Pathways from Anxiety Symptomology in Early Adolescence to Risk for Adverse Patterns of Substance Use” funded through the National Institute on Drug Abuse, UNC School of Medicine and Frank Porter Graham Child Development Institute at UNC-Chapel Hill researchers will examine the neural and physiological mechanisms associated with emergence of substance use in adolescence who experience anxiety.

    Aysenil Belger, PhD, professor in the UNC Department of Psychiatry and director of the Clinical Translational Core UNC Intellectual and Developmental Disabilities Research Center; and Diana Fishbein, PhD, senior scientist and director of translational neuro-prevention research at the Frank Porter Graham Child Development Institute at UNC-Chapel Hill, are co-principal investigators leading a team of researchers to examine cognitive functions, stress physiology and brain circuits and functions that distinguish adolescents with anxiety who do and do not go on to use psychoactive substances, including alcohol, during adolescence.

    Researchers will recruit children ages 12-14 who report symptoms of anxiety. The cohort will then be stratified based on a tool developed by co-PI Ty Ridenour, PhD, senior research analyst at RTI International and co-PI; the tool focuses on risk factors such as home life, peer influences, cognitive functioning, impulsivity, risk-taking, and other behaviors to determine if the child has the individual profile that places them at risk of transitioning to substance use. Researchers will compare brain function and stress physiological systems in adolescents who do and do not initiate substance use over five years.

    This longitudinal study is testing participants at baseline,12 months and 24 months. Adolescents will be studied using magnetic resonance imaging (MRI) while performing tasks that measure cognitive control, impulsivity, and executive decision-making. Their physiological responses to social stressors, including heart rate, perspiration, and changes in the stress hormone, cortisol, will also be measured. In-depth surveys and toxicology screens are used to determine substance use patterns and a wide range of other child characteristics. The first goal is to first identify the predictors of adverse patterns of substance use in adolescents with anxiety symptoms and, second, to determine what neurobiological mechanisms drive this association. This information will enable the development of more targeted, personalized interventions to prevent pathways of substance use.

    “We have very little understanding of the biological differences that explain why some people are prone to substance use or why some children and adolescents get to the point of substance use while others don’t,” Belger said. “Once we find these biological markers, we can identify those at increased risk and what the risk factors are for that individual, and we can develop interventions that enhance cognitive skills or intervene with stress management to keep them off the adverse trajectory, using prevention science.”

    Fishbein said, “When young people experience anxiety symptoms, it can compromise the ability of interventions to prevent substance use from developing. In adding to our knowledge about biological processes that underlie anxiety and how they relate to substance use, this study will help us to identify windows of opportunity during child and adolescent development when we can most effectively intervene.”

    Although this study focuses on biological “risks” that may propel youth toward substance use, the researchers will also identify protective factors, such as strong connections between cognitive and emotional centers of the brain or supportive social networks that may reduce risk and lead to more positive outcomes for children with anxiety.

    Given that a child’s brain is very sensitive to early experiences, identifying conditions that have positive effects should reveal opportunities for strengthening those protective factors to avoid pathways to negative outcomes.

    “This research is timely and important,” Belger added. “Post-pandemic anxiety and mental health issues in adolescents are on the rise, and many of the same characteristics we’re studying also contribute to other mental health issues like suicidality. Our study results could identify more than just risk for substance use. There are policy implications as well, including identifying social, structural, and systemic risk factors that contribute to anxiety and substance use.”

    Belger, who had directed the Frank Porter Graham Child Development Institute (FPG) for five years, is focused on understanding neurobiological systems, functions and mechanisms that contribute to the development of psychopathology in youth. She works on the biology of high-risk integrating multimodal methodologies such as brain imaging, electrophysiological recordings, and cognitive behavioral assessments.

    Fishbein’s career has centered on understanding factors that contribute to the development of psychopathology, focusing on adverse experiences that predict negative outcomes, including substance abuse. She is particularly interested in how evidence-based interventions and policies have the potential to normalize developmental trajectories, leading to positive behavioral and mental health outcomes.

    Ridenour’s groundbreaking work focuses on translating problem behavior etiology research into clinical tools to improve prevention integrating advanced statistical analysis for longitudinal clinical trials.

    Together, the work of Belger, Fishbein, and Ridenour applies technologies and findings from neuroscience to address outstanding questions in the field of prevention, leading to more effective methods and policy reforms to support the health and well-being of our young people.

    The researchers want to bridge with other collaborators studying brain function in adolescents in other circumstances. The team is excited to hear from others who want to add measures to ancillary projects. The researchers are also interested in clinical collaborations for recruitment but also for referral of vulnerable children. To join the collaboration to become a resource for psychoeducation for families, reach out to Aysenil Belger.

    UNC Psychiatry contact: Samantha Weiss

    UNC School of Medicine contact: Mark Derewicz

    University of North Carolina School of Medicine

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  • New Research Shows HIV Can Lie Dormant in the Brain

    New Research Shows HIV Can Lie Dormant in the Brain

    Newswise — CHAPEL HILL, N.C. – As a part of its life cycle, the human immunodeficiency virus-1 (HIV) inserts a copy of its DNA into human immune cells. Some of these newly infected immune cells can then transition into a dormant, latent state for a long period of time, which is referred to as HIV latency.

    Although current therapies, such current antiretroviral therapy (ART), can successfully block the virus from replicating further, it cannot eradicate latent HIV. If treatment is ever discontinued, the virus can rebound from latency and reignite the progression of HIV infection to AIDS.

    Scientists from the HIV Cure Center at the UNC School of Medicine, University of California San Diego, Emory University, and University of Pennsylvania have been searching for where exactly these latent cells are hiding in the body. New research published in the Journal of Clinical Investigations confirms that microglial cells – which are specialized immune cells with a decade-long lifespan in the brain – can serve as a stable viral reservoir for latent HIV.

    “We now know that microglial cells serve as a persistent brain reservoir,” said first author Yuyang Tang, PhD, assistant professor of medicine in the Division of Infectious Diseases and member of the UNC HIV Cure Center. “This had been suspected in the past, but proof in humans was lacking. Our method for isolating viable brain cells provides a new framework for future studies on reservoirs of the central nervous system, and, ultimately, efforts towards the eradication of HIV.”

    Latent HIV

    HIV is a tricky and unique virus to study. During infection, the virus specifically targets the key coordinators of the immune response, which are called CD4+ lymphocytes. Over time, the virus kills enough CD4+ cells to cause immunodeficiency. .

    Past research has shown that latent HIV can hide within a few of the surviving CD4+ T cells throughout the body and the bloodstream. However, other viral reservoirs have been suspected to hide within the central nervous system (CNS) in people with HIV receiving effective ART.

    Unlike peripheral blood cells, it is extremely difficult to access and analyze brain tissues for the study of HIV reservoirs. Since these types of cells cannot be safely sampled in people taking ART,he potential viral reservoir in the brain has remained an enigma for many years.

    Extracting Pure Brain Tissue

    The team first studied the brains of macaques with the simian immunodeficiency virus (SIV), a virus that is closely related to HIV, from the Yerkes National Primate Research Center at Emory University to get a better understanding of how to extract and purify viable cells from primate brain tissue.

    Researchers used physical separation techniques and antibodies to selectively remove cells that were expressing microglial surface markers. Then, they isolated and separated the highly pure brain myeloid cells from the CD4+ cells that were passing through the brain tissue.

    Using these techniques, researchers then obtained samples that were donated by HIV+ people who were enrolled in “The Last Gift” Study at the University of California San Diego (UCSD). As a part of this unique and important effort, altruistic HIV+ people, who aretaking ART but suffering from other terminal illnesses, will their bodies to further the HIV research project.

    “The samples are from people living with HIV, who are on therapy but facing a fatal disease of some kind,” said the co-author David Margolis, MD, the Sarah Kenan Distinguished Professor of Medicine, Microbiology & Immunology, and Epidemiology. “They were willing to not just donate their bodies to science, but also participate in the research program in the months leading up to their death. It’s an extraordinary program that made this critical research possible.”

    Now that the researchers know that latent HIV can take refuge in microglial cells in the brain, they are now considering plans to target this type of reservoir. Since latent HIV in the brain is radically different from the virus in the periphery, researchers believe that it has adapted special characteristics to replicate in the brain.

    “HIV is very smart,” said senior author Guochun Jiang, PhD, assistant professor in the UNC Department of Biochemistry and Biophysics and member of the UNC HIV Cure Center. “Over time, it has evolved to have epigenetic control of its expression, silencing the virus to hide in the brain from immune clearance. We are starting to unravel the unique mechanism that allows latency of HIV in brain microglia”.”

    NF-κB signaling is one of the critical signaling pathways that controls HIV expression elsewhere in the body. When NF-κB signaling is ”turned off”, HIV enters latency in the peripheral blood. However, it seems that latent HIV in the brain is not impacted by the activation of NF-κB signaling. Researchers are unsure why that is, but once an answer is found, they will be one step closer to knowing how to selectively target and eradicate the virus in the brain or peripheral blood.In addition to understanding the inner workings of the brain reservoir, the researchers are also trying to determine the true size of the latent HIV brain reservoir. 

    “It is very hard to know how big the reservoir is,” said Margolis, who is also the director of the UNC HIV Cure Center. “The problem with trying to eradicate HIV is like trying to eradicate cancer. You want to be able to get it all, so it won’t come back.”

    About UNC School of Medicine The UNC School of Medicine (SOM) is the state’s largest medical school, graduating more than 180 new physicians each year. It is consistently ranked among the top medical schools in the US, including 7th overall for primary care by US News & World Report, and 7th for research among public universities. More than half of the school’s 1,700 faculty members served as principal investigators on active research awards in 2021. Two UNC SOM faculty members have earned Nobel Prize awards.

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  • UNC Researchers Receive NIH Grant to Study Drug-Resistant Malaria in Ethiopia

    UNC Researchers Receive NIH Grant to Study Drug-Resistant Malaria in Ethiopia

    Newswise — CHAPEL HILL, NC – Ethiopia is Africa’s second most-populated country with an estimated 60% of its population at risk for malaria exposure. Plasmodium falciparum infection accounts for the majority of malaria deaths and approximately 70% of all cases. Artemisinin-based combination therapies (ACTs) have been critical to the success in reducing the global burden of falciparum malaria between 2000 and 2015. But the emergence and spread of artemisinin-resistant falciparum malaria has become a major threat to global elimination.

    “Ethiopia has made meaningful gains in the fight against malaria. However, the malaria parasite has a long history of evolving to survive, and it appears to be doing just that,” said Jonathan Parr, MD, MPH, assistant professor of medicine in infectious diseases at the UNC School of Medicine.

    The project “Epidemiology and Determinants of Emerging Artemisinin-Resistant Malaria in Ethiopia,” has been awarded 3.6 million in NIH R01 funding, building upon UNC-Chapel Hill’s strong partnership with the Ethiopian Public Health Institute (EPHI), the technical arm of the Ethiopia Federal Ministry of Health. The project also includes partners at Brown University, University of Notre Dame, and Imperial College London. Parr described the study as an exciting opportunity to use cutting-edge, multidisciplinary science in the fight against malaria.

    “We will be sequencing parasites from a network of sites across the country, conducting laboratory experiments, and performing predictive modeling to understand how dangerous new strains of malaria emerge and spread,” he said.

    Ashenafi Assefa, PhD, who trained as a UNC postdoctoral researcher in Dr. Parr’s group and has years of experience conducting translational malaria research, will lead study activities in Ethiopia, training personnel and running assays while overseeing protocol implementation and data collection. Assefa said the research outcomes will contribute to the advancement of scientific knowledge in the field.

    “This study is expected to generate critical evidence about the rise and expansion of drug-resistant parasites in the region,” said Assefa. “The results will be readily consumed by policymakers and advance malaria elimination efforts in Ethiopia and beyond.”

    Collaborating with EPHI, researchers will conduct surveys of people presenting to health facilities with falciparum malaria across Ethiopia to characterize resistant parasites. These results will be integrated into a point-of-care clinical tool for identifying individuals with drug-resistant falciparum malaria. The results will also guide the development of a model to predict the future spread of resistance mutations.

    Jon Juliano, MD, MSPH, heads the Infectious Disease Epidemiology and Ecology Lab at UNC, an interdisciplinary research collaboration that explores how pathogens interact with human hosts, with a focus on malaria.

    “We are entering a period of great concern about the effectiveness of antimalarial drugs in East Africa,” Juliano said. “The emergence of partial artemisinin resistance in multiple countries in the Rift Valley raises concerns about the long-term utility of these first line agents. This project represents a significant extension of studies to understand the emergence and spread of these mutations that the University of North Carolina is either leading or supporting in Rwanda, Uganda, Tanzania, the Democratic Republic of the Congo and now Ethiopia.”

    The UNC Institute for Global Health and Infectious Diseases (IGHID) at the UNC School of Medicine is an engine for global health research and pan-university collaboration, transforming health in North Carolina and around the world. IGHID facilitates research excellence while providing opportunities for investigators to nurture emerging scientists through training and service, to achieve positive patient care outcomes and practice.

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  • A New Strategy to Break Through Bacterial Barriers in Chronic Treatment-Resistant Wounds

    A New Strategy to Break Through Bacterial Barriers in Chronic Treatment-Resistant Wounds

    Newswise — CHAPEL HILL, N.C. – Chronic wounds are open sores or injured tissue that fail to heal properly. These types of wounds are notoriously challenging to treat because of bacterial infections like Staphylococcus aureus, or S. aureus. Additionally, bacterial infections that are highly resistant to antibiotics, such as methicillin-resistant S. aureus (MRSA), are one of the main causes of life-threatening infections in hospital patients.

    To defend itself from our immune system and other threats, S. aureus can band together, creating a slick, slimy forcefield – or biofilm – around itself. The biofilm barrier is so thick that neither immune cells nor antibiotics can penetrate through and neutralize the harmful bacteria.

    Researchers at the UNC School of Medicine and the UNC-NC State Joint Department of Biomedical Engineering have developed a new method that combines palmitoleic acid, gentamicin, and non-invasive ultrasound to help improve drug delivery in chronic wounds that have been infected with S. aureus.

    Using their new strategy, researchers were able to reduce the challenging MRSA infection in the wounds of diabetic mice by 94%. They were able to completely sterilize the wounds in several of the mice, and the rest had significantly reduced bacterial burden. Their results were published in Cell Chemical Biology.

    “When bacteria are not completely cleared from chronic wounds, it puts the patient at high risk for the infection recurring or of developing a secondary infection,” said senior author Sarah Rowe-Conlon, PhD, a research associate professor in the Department of Microbiology and Immunology. “This therapeutic strategy has the potential to improve outcomes and reduce relapse of chronic wound infections in patients. We are excited about the potential of translating this to the clinic, and that’s what we’re exploring right now.”

    Biofilms act as a physical barrier to many classes of antibiotics. Virginie Papadopoulou, PhD, a research assistant professor in the UNC-NCSU Joint Department of Biomedical Engineering, was curious to know if non-invasive cavitation-enhanced ultrasound could create enough agitation to form open spaces in the biofilm to facilitate drug-delivery.

    Liquid droplets which can be activated by ultrasound, called phase change contrast agent (PCCA), are applied topically to the wound. An ultrasound transducer is focused on the wound and turned on, causing the liquid inside the droplets to expand and turn into microscopic gas-filled microbubbles, when then move rapidly.

    The oscillation of these microbubbles agitates the biofilm, both mechanically disrupting it as well as increasing fluid flow. Ultimately, the combination of the biofilm disruption and the increased permeation of the drugs through the biofilm allowed the drugs to come in and kill the bacterial biofilm with very high efficiency.

    “Microbubbles and phase change contrast agents act as local amplifiers of ultrasound energy, allowing us to precisely target wounds and areas of the body to achieve therapeutic outcomes not possible with standard ultrasound,” said Dayton, the William R. Kenan Jr. Distinguished Professor and Department Chair of the UNC-NCSU Joint Department of Biomedical Engineering. “We hope to be able to use similar technologies to locally delivery chemotherapeutics to stubborn tumors or drive new genetic material into damaged cells as well.”

    When the bacterial cells are trapped inside the biofilm, they are left with little access to nutrients and oxygen. To conserve their resources and energy, they transition into a dormant or sleepy state. The bacteria, which are known as persister cells in this state, are extremely resistant to antibiotics.

    Researchers chose gentamicin, a topical antibiotic typically ineffective against S. aureus due to widespread antibiotic resistance and poor activity against persister cells. The researchers also introduced a novel antibiotic adjuvant, palmitoleic acid, to their models.

    Palmitoleic acid, an unsaturated fatty acid, is a natural product of the human body that has strong antibacterial properties. The fatty acid embeds itself into the membrane of bacterial cells, and the authors discovered that it facilitates the antibiotic’s successful entry into S. aureus cells and is able to kill persister cells and reverse antibiotic resistance.

    Overall, the team is enthusiastic about the new topical, non-invasive approach because it may give scientists and doctors more tools to combat antibiotic resistance and to lessen the serious adverse effects of taking oral antibiotics.

    “Systemic antibiotics, such as oral or IV, work very well, but there’s often a large risk associated with them such as toxicity, wiping out gut microflora and C. difficile infection,” said Rowe-Conlon. “Using this system, we are able to make topical drugs work and they can be applied to the site of infection at very high concentrations, without the risks associated with systemic delivery.”

     

    About UNC School of Medicine

    The UNC School of Medicine (SOM) is the state’s largest medical school, graduating more than 180 new physicians each year. It is consistently ranked among the top medical schools in the US, including 5th overall for primary care by US News & World Report, and 6th for research among public universities. More than half of the school’s 1,700 faculty members served as principal investigators on active research awards in 2021. Two UNC SOM faculty members have earned Nobel Prize awards.

    About the Joint Department of Biomedical Engineering

    The Joint Department is ranked in the top 10 biomedical engineering programs in the US by the Blue Ridge Institute for Medical Research, top 20 biomedical engineering programs worldwide by the Shanghai Academic Ranking of World Universities, and is a top 5 institution for total bachelor’s degrees awarded in biomedical engineering (ASEE).

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  • Scientists Publish New Findings in Quest to Build a Better Opioid

    Scientists Publish New Findings in Quest to Build a Better Opioid

    Newswise — CHAPEL HILL, NC – In the continuing effort to improve upon opioid pain relievers, American and Chinese scientists used cryoEM technology to solve the detailed structures of the entire family of opioid receptors bound to their naturally occurring peptides. Subsequent structure-guided biochemical studies were then performed to better understand the mechanisms of peptide-receptor selectivity and signaling drugs.

    This work, published in Cell, provides a comprehensive structural framework that should help drug developers rationally design safer drugs to relieve severe pain.

    This work was spearheaded by the lab of Eric Xu, PhD, at the CAS Key Lab of Receptor Research in China, in collaboration with the lab of Bryan L. Roth, MD, PhD, at the UNC School of Medicine, where graduate student Jeff DiBerto led the pharmacological experiments to understand the receptors’ signaling mechanisms.

    Opioid drugs relieve pain by mimicking a naturally occurring pain-relief function within our nervous symptoms. They are the best, strongest pain relievers we have. Unfortunately, they come with side effects, some severe such as numbness, addiction, and respiratory depression, leading to overdose deaths.

    Scientists have been trying for many years to overcome the side-effect problem in various ways, all involving one or more of four opioid receptors to no avail. One way scientists continue to explore is the creation of peptide or peptide-inspired small molecule drugs.

    Peptides are short chains of amino acids; think of them as short proteins. Certain naturally occurring, or endogenous, peptides bind to opioid receptors on the surface of cells to create an analgesic effect, also known as pain relief. Think of an analgesic like an anesthetic, except that analgesics do not “turn off” the nerves to numb the body or alter consciousness. So, the idea is to create a peptide drug that has a strong analgesic effect, without numbing nerves or altering consciousness or causing digestive, respiratory, or addiction issues.

    “The problem in the field is we’ve lacked the molecular understanding of the interplay between opioid peptides and their receptors,” said Roth, co-senior author and the Michael Hooker Distinguished Professor of Pharmacology. “We’ve needed this understanding in order to try to rationally design potent and safe peptide or peptide-inspired drugs.”

    Using cryogenic electron microscopy, or cryoEM, and a battery of biomechanistic experiments in cells, the Xu and Roth labs systematically solved the detailed structures of endogenous peptides bound to all four opioid receptors. These structures revealed details and insights into how specific naturally occurring opioid peptides selectively recognize and activate opioid receptors. The researchers also used exogenous peptides, or drug-like compounds, in some of their experiments to learn how they activate the receptors.

    The cryoEM structures of agonist-bound receptors in complex with their G protein effectors (called their “active state”) represents what these receptors look like when they are signaling in cells, giving a detailed view of peptide-receptor interactions. The Roth lab used the structures solved by the Xu lab to guide the design of mutant receptors, and then tested these receptors in biochemical assays in cells to determine how they alter receptor signaling. Understanding these interactions can then be used to design drugs that are selective for opioid receptor subtypes, as well as to produce certain signaling outcomes that may be more beneficial than those of conventional opioids.

    “This collaboration revealed conserved, or shared, mechanisms of activation and recognition of all four opioid receptors, as well as differences in peptide recognition that can be exploited for creating subtype-selective drugs,” said DiBerto, first author and PhD candidate in the Roth lab. “We provide more needed information to keep pushing the field forward, to answer basic science questions we hadn’t been able to answer before now.”

    Previous research showed the structure of opioid receptors in their inactive or active-like states, with active state structures only existing for the mu-opioid receptor subtype, the primary target of drugs like fentanyl and morphine. In the Cell paper, the authors show agonist-bound receptors in in complex with their G protein effectors, made possible through cryoEM technology that did not exist when currently used medications were being developed.

    Drugs such as oxycontin, oxycodone, and morphine cause various effects inside cells and throughout the nervous symptom, including pain relief. But they have effects in the digestive and respiratory systems, too, and interact with cells to lead to addiction. Fentanyl, meanwhile, is another powerful pain reliever, but it binds to opioid receptors in such a way as to cause severe side effects, including the shutdown of the respiratory system.

    The thrust behind such research led by Xu and Roth is to home in on the mechanistic reasons for pain relief potency without triggering the cellular mechanisms that lead to severe side effects and overdosing.

    “We are attempting to build a better kind of opioid,” Roth says, “We’re never going to get there without these kind of basic molecular insights, wherein we can see why pain is relieved and why side effects occur.”

    Co-first authors of the Cell paper are Yue Wang and Youwen Zhuang of the CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research at the Shanghai Institute of Materia Medica in the Chinese Academy of Sciences. Other authors are Edward Zhou and Karsten Melcher of the Van Andel Research Institute in Grand Rapids, MI, Gavin Schmitz and Manish Jain at the UNC School of Medicine, and Qingning Yuan, Weiyi Liu, and Yi Jiant at the CAS Key Laboratory.

    University of North Carolina School of Medicine

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  • Scientists Discover Protein Partners that Could Heal Heart Muscle

    Scientists Discover Protein Partners that Could Heal Heart Muscle

    Newswise — CHAPEL HILL, N.C. – Scientists at the UNC School of Medicine have made a significant advance in the promising field of cellular reprogramming and organ regeneration, and the discovery could play a major role in future medicines to heal damaged hearts.

    In a study published in the journal Cell Stem Cell, scientists at the University of North Carolina at Chapel Hill discovered a more streamlined and efficient method for reprogramming scar tissue cells (fibroblasts) to become healthy heart muscle cells (cardiomyocytes). Fibroblasts produce the fibrous, stiff tissue that contributes to heart failure after a heart attack or because of heart disease. Turning fibroblasts into cardiomyocytes is being investigated as a potential future strategy for treating or even someday curing this common and deadly condition.

    Surprisingly, the key to the new cardiomyocyte-making technique turned out to be a gene activity-controlling protein called Ascl1, which is known to be a crucial protein involved in turning fibroblasts into neurons. Researchers had thought Ascl1 was neuron-specific.

    “It’s an outside-the-box finding, and we expect it to be useful in developing future cardiac therapies and potentially other kinds of therapeutic cellular reprogramming,” said study senior author Li Qian, PhD, associate professor in the UNC Department of Pathology and Lab Medicine and associate director of the McAllister Heart Institute at UNC School of Medicine.

    Scientists over the last 15 years have developed various techniques to reprogram adult cells to become stem cells, then to induce those stem cells to become adult cells of some other type. More recently, scientists have been finding ways to do this reprogramming more directly – straight from one mature cell type to another. The hope has been that when these methods are made maximally safe, effective, and efficient, doctors will be able to use a simple injection into patients to reprogram harm-causing cells into beneficial ones.

    “Reprogramming fibroblasts has long been one of the important goals in the field,” Qian said. “Fibroblast over-activity underlies many major diseases and conditions including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and the scar-like brain damage that occurs after strokes.”

    In the new study, Qian’s team, including co-first-authors Haofei Wang, PhD, a postdoctoral researcher, and MD/PhD student Benjamin Keepers, used three existing techniques to reprogram mouse fibroblasts into cardiomyocytes, liver cells, and neurons. Their aim was to catalogue and compare the changes in cells’ gene activity patterns and gene-activity regulation factors during these three distinct reprogrammings.

    Unexpectedly, the researchers found that the reprogramming of fibroblasts into neurons activated a set of cardiomyocyte genes. Soon they determined that this activation was due to Ascl1, one of the master-programmer “transcription factor” proteins that had been used to make the neurons.

    Since Ascl1 activated cardiomyocyte genes, the researchers added it to the three-transcription-factor cocktail they had been using for making cardiomyocytes, to see what would happen. They were astonished to find that it dramatically increased the efficiency of reprogramming – the proportion of successfully reprogrammed cells – by more than ten times. In fact, they found that they could now dispense with two of the three factors from their original cocktail, retaining only Ascl1 and another transcription factor called Mef2c.

    In further experiments they found evidence that Ascl1 on its own activates both neuron and cardiomyocyte genes, but it shifts away from the pro-neuron role when accompanied by Mef2c. In synergy with Mef2c, Ascl1 switches on a broad set of cardiomyocyte genes.

    “Ascl1 and Mef2c work together to exert pro-cardiomyocyte effects that neither factor alone exerts, making for a potent reprogramming cocktail,” Qian said.

    The results show that the major transcription factors used in direct cellular reprogramming aren’t necessarily exclusive to one targeted cell type.

    Perhaps more importantly, they represent another step on the path towards future cell-reprogramming therapies for major disorders. Qian says that she and her team hope to make a two-in-one synthetic protein that contains the effective bits of both Ascl1 and Mef2c, and could be injected into failing hearts to mend them.

    “Cross-lineage Potential of Ascl1 Uncovered by Comparing Diverse Reprogramming Regulatomes” was co-authored by Haofei Wang, Benjamin Keepers, Yunzhe Qian, Yifang Xie, Marazzano Colon, Jiandong Liu, and Li Qian.

    Funding was provided by the American Heart Association and the National Institutes of Health (T32HL069768, F30HL154659, R35HL155656, R01HL139976, R01HL139880).

    University of North Carolina School of Medicine

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