Who said engineering and neuroscience aren’t good bedfellows?

Two University of South Florida professors are proof that disparate disciplines can work together for a common cause – gaining a better understanding of a common health emergency.

Ashwin Parthasarathy, Ph.D., assistant professor in the Department of Electrical Engineering, and Maxim Mokin, M.D., Ph.D., associate professor in the Department of Neurosurgery and Brain Repair, are collaborating on a device that could help prevent strokes in patients during surgery.

(L-r) Dr. Ashwin Parthasarathy, PhD, and Dr. Maxim Mokin, MD, PhD, at Tampa General Hospital as Dr. Parthasarathy tests probes for electrical activity.

“We’re looking to see how new technologies can help drive patient care,’’ Dr. Parthasarathy said of their multi-disciplinary work. “As an engineer, I’m interested in the technology aspect and as a neurologist, Maxim is interested in the medical aspect. But I can address what his needs are and come up with solutions.’’

The engineering department is on the USF campus in northeast Tampa, while much of the work in neurology takes place downtown, at the USF Health South Tampa Center and Tampa General Hospital, USF Health’s primary teaching partner. Traditionally, most teamwork among scientists is done in closer proximity.

“It’s quite rare to be doing this because physically, we don’t even run into each other on campus,’’ Dr. Mokin said. “Engineers live and breathe in their silos and we clinicians don’t get exposed to what they do.’’

The faculty members recently were awarded a two-year, $400,000 research grant from the National Institute of Neurological Disorders and Stroke, a part of the National Institutes of Health. The money will help them collect more quantitative data from their new device, with the goal of improving treatment for patients. They also will purchase tools to refine the technology and make it fully automated, capture more data points, and hire a research coordinator.

“We’re working to make it more robust and easy to use,’’ Dr. Parthasarathy said.

Called a DCS − for diffuse correlation spectroscopy − the optical monitoring tool uses fiber optics to emit light and capture a returning signal. The light monitors blood flow to the brain during surgery and gives real-time information. Any abnormalities in how the light travels alerts doctors to a potential problem, such as a stroke or brain bleed. An explanation of their initial research findings has been published in the Journal of NeuroInterventional Surgery.

For years, neurologists have used MRIs, CAT scans and transcranial dopplers to take images of the brain, but these don’t always give surgeons the information they need at a precise moment. The new, non-invasive device – which has been tested on more than a dozen patients at TGH − uses small plastic caps attached to the head that send real-time data to a monitor in the operating room.

An image of the before (left) and after treatment delivered at Tampa General Hospital.

“The others are good tools but they’re bulky and only give you a snapshot,’’ Dr. Mokin said. “This is a small portable device that studies brain functions in an acute setting, and it gives a continuous recording.’’

The faculty members believe their invention could be a breakthrough in a critical aspect of health care. Each year, nearly 800,000 people in the United States suffer a stroke – one every 40 seconds, according to the American Heart Association. The majority of these incidents are ischemic, meaning blood flow to the brain is reduced or blocked.

“This device is giving us more data to better understand brain signals that might indicate a stroke,’’ Dr. Mokin said. “We need to know more about what is noise, what is normal function, what are the thresholds, and what changes indicate that something bad is about to happen.’’

The more information gathered in the operating room the better, the doctors say, as it will lead to efficiencies on the engineering bench.

“It’s an exciting way to do science,’’ Dr. Parthasarathy said. “I’m able to get instantaneous feedback on how my device is working, so it’s not just me toiling alone in the lab.

“Our hope is to show how this technology has great clinical value, maybe by predicting if a patient is getting better or worse. That’s the end game − predictive value in our measurements.’’

– Story by Kurt Loft for USF Health News; photos by Allison Long, USF Health Communications 

Until recently, scientists knew little about how important cells called fibroblasts might help protect the brain when a life-threatening bleeding stroke occurs.

But these cells may function like a plumber making an emergency house call, said Yao Yao, PhD, associate professor in Molecular Pharmacology and Physiology in the USF Health Morsani College of Medicine.

The analogy may help explain the healing power of fibroblasts, a type of cell that contributes to the formation of connective tissue.

Little has been known about fibroblasts in the brain until recently. But studying how they function there – and their healing power on the protective sheath called the blood-brain barrier (BBB) – could hold an important key to mitigating damage done by hemorrhagic strokes, for which there is currently no treatment, making them the deadliest kind of strokes.

“In the small vessels or capillaries of your brain, you normally don’t have any fibroblasts there because the vessels are tight – not leaky,” Dr. Yao said. “It’s like a home where all the plumbing system works perfectly. But when there’s a neurological disorder like a stroke, these small vessels become leaky and toxic blood components enter the brain. And we have found that fibroblasts travel from the large vessels to the small vessels, and repair a BBB injury.”

That, he explained, is the equivalent to fibroblasts serving as a plumber coming to fix broken pipes, with water suddenly pouring into the house.

“What we know so far is that the fibroblasts are functioning like the plumber,” Dr. Yao said. “They come. They repair damage. And then they leave.”

(Sadly, the plumber alluded to in the headline above, who achieved cartoon fame in the children’s TV show The Electric Company by telling a parrot, “It’s the plumber – I’ve come to fix the sink,” does not manage this kind of dignified departure.)

Dr. Yao and his team recently published their findings about fibroblasts (sans parrots) in the journal Cell Reports.

Some aspects of fibroblasts have been thoroughly studied, such as how these cells contribute to connective tissue in the skin. But for many years, scientists didn’t know that fibroblasts could be found within the brain or central nervous system. They were thought to exist only on the surface of the brain, in layers of the protective membrane called the meninges.

“But in 2018, there was a breakthrough with a report that said fibroblasts did exist in the brain, not just on the surface,” Dr. Yao said. “So the big question for us then was, ‘What do they do? What is their function?’ From skin studies, we knew that fibroblasts are known to repair injuries if, for instance, we cut ourselves. So in the brain, does the fibroblast do the same thing?”

This prompted Yao and his colleagues to conduct a thorough search of the existing literature about fibroblasts, which was limited to “four or five papers over the past 100 years,” he said.

Complicating the matter was that most existing studies utilized non-specific markers to identify the fibroblasts.

“Most fibroblast markers also label other cell populations,” Dr. Yao said. “When these markers are used, it is difficult to determine if fibroblasts or other cells are involved.”

That led Dr. Yao’s group to study the 2018 paper, in which a marker unique to fibroblasts – known as collagen one-alpha-one (Col 1α1) was identified. That was the key step in starting their own work, leading in time to a significant discovery.

“We found out that fibroblasts do repair a very important structure called the blood-brain barrier – the area that separates blood from the central nervous system, the brain and spinal cord,” he said. “This is so important, because blood-brain barrier disruption is found in almost all neurological disorders – anything you can think of.”

Furthermore, they knew that after a brain injury or neurological disorder, it is critical to repair the disruption as quickly as possible. Tests were soon conducted on laboratory mice. Those mice deprived of fibroblasts experienced significant blood brain-barrier leakage and died within a week; those with fibroblasts recovered.

“So we had evidence,” he said. “The collagen one-alpha-one fibroblasts – in this population of mice – functioned to repair the BBB after hemorrhagic stroke.”

What comes next?

“Our goal is to fully understand the molecular mechanisms of fibroblast-mediated BBB repair, so that we can find a way to target fibroblasts to minimize neurological damage,” Yao said. “With this knowledge, we can signal fibroblasts to either come more quickly to repair BBB injury – mostly in the early phase of disease – or leave small vessels after the BBB is repaired to avoid fibrosis, which occurs mostly in the late phase of disease.”

Fibrosis can result when fibroblasts linger too long, causing a thickening or scarring of connective tissue. That led Dr. Yao back to his analogy.

“You wouldn’t want a plumber just to stay in your house when the job is done, either, just as you don’t want fibroblasts staying around when they complete their repair,” Dr. Yao said. He extends the comparison further. He and his team have learned that the fibroblasts accomplish their BBB repair by secreting a protein called TIMP2.

“Think of that as the plumber’s main tool for the job,” he said.

In addition to hoping to learn how to signal fibroblasts, Dr. Yao said he and his team will be looking into the future possibility of injecting TIMP2 directly to the injured brain, and circumventing the need for fibroblasts to deliver it.

Yao gives special credit to Lingling Xu, PhD, who played a leading role in the research and Cell Reports paper, and is now a post-doctoral researcher at Emory University. They worked together at the University of Georgia before Dr. Yao came to USF in 2021. “Our whole team will continue studying fibroblasts,” Dr. Xu said. “There’s still a long way to go to fully understand this cell.”

Meanwhile, they all know how high the stakes are in their research.

“When a hemorrhagic stroke happens, there’s not even one treatment for it, unlike ischemic strokes,” Dr. Yao said. “It is a leading cause of death. And hopefully our research will lead to saving many lives.”

— by Dave Scheiber for USF Health Communications

It is a part of the heart that most people have never pondered, let alone heard of, in their lives. But the left atrial appendage – a physical trait that all humans share – is worth knowing about because it is involved in the vast majority of strokes. Now, a prestigious new grant obtained by a team from the USF Health Morsani College of Medicine and Tampa General Hospital could significantly enhance preventive treatments.

Thanks to the innovative work of Dr. Hiram Bezerra, professor at the USF Health Morsani College of Medicine and director of the TGH Interventional Cardiology Center of Excellence, the $460,000 grant could lead to key improvements of an existing procedure to block the opening to the left atrial appendage (LAA) in certain patients who are at high risk for stroke. And it ultimately could deliver safer, faster, and more effective results for patients.

This marks the first time a National Institutes of Health R01 grant – designed to support advanced, hypothesis-driven research projects with strong preliminary data – has been awarded to USF Health’s Division of Cardiology Sciences in the Morsani College of Medicine.

“I think this is reflective of the journey we are on to become a national presence in the forefront of cardiology,” said Dr. Guilherme Oliveira, chief of the division and Ed C. Wright Professor and Chair of Cardiovascular Research, as well as co-director of the USF Heart Institute for Research. Dr. Oliveira also is vice president and chief of the Tampa General Hospital Heart & Vascular Institute.

“This has never been done here before – the ability to get an R01 grant for our division that basically is developing a new technology – with potential clinical applications going all the way from basic pre-clinical engineering of an innovation and taking it all the way to the bedside,” said Dr. Oliveira. “And I think it’s very telling of where we are with the type of talent we’ve been able to attract to USF and Tampa General.”

In this case, the grant, three years in the works, will allow Dr. Bezerra and his team to produce a better, more streamlined approach for dealing with the left atrial appendage – an area in the heart’s left atrium akin to a little pocket. While the structure may help lower pressure in the atrium, it also is possible for blood to pool there in patients with atrial fibrillation, a type of irregular heartbeat, and raises the risk of a clot that could travel to the brain.

“The actual magical aspect of it, and what we are trying to achieve, is a therapy that is offered for stroke prevention,” said Dr. Bezerra. “More than 90 percent of strokes originate from the left atrial appendage chamber. And by occluding the left atrial appendage, you will prevent a stroke in a population prone to have one – the atrial fibrillation, or AFib, population.”

Those suffering from AFib experience an array of symptoms that include an irregular heartbeat, a racing heart, shortness of breath, fatigue and chest pain. People with the condition are some five times more likely to suffer a stroke than those without it – with some 12 million in the U.S. estimated to have AFib by 2030.

“The patients we are targeting have AFib and for some reasons are not a good candidate for the standard preventive therapy of blood thinners,” Dr. Bezerra added. “The next treatment in line is occluding the left atrial appendage. And we are talking about hundreds of thousands of patients in the United States.”

The primary device in the U.S. used to block the left atrial appendage is called the Watchman, manufactured by Boston Scientific, with some doctors employing the Amplatzer Amulet heart device from Abbott. In the current protocol, a patient typically receives a transesophageal echocardiogram two weeks ahead of the procedure to examine the structure and functioning of the heart and evaluate the size of the appendage.

This allows doctors to plan the procedure and select the device. Patients commonly receive general anesthesia for the procedure, which again involves a transesophageal echocardiogram as a real-time guide. In most cases, patients return home the next day.

“But we are pushing to implement a workflow that is less resource intense, and that we believe is actually safer to do,” Bezerra said.

The grant proposed that patients will not have to undergo general anesthesia for the procedure, and a single cardiac MRI would be employed, allowing a patient to just come in once and not have to undergo a separate pre-imaging appointment. The scanner on the day of the procedure would perform the sizing to determine the best device to use. And it would also allow for improved visibility in real-time guidance during the procedure – providing live, higher-resolution images than the current method affords.

“It will all be done with a single modality,” Dr. Bezerra explained. “In addition, the patient is awake. There is no additional cost of the intracardiac echo, or the inconvenience of general anesthesia. And it increases the chances of a patient to go home the same day.”

Dr. Bezerra wrote the grant to be tied specifically to the Watchman because it is more frequently used. But ultimately, replicating the procedure on a different device would not be difficult to achieve. The grant includes a pre-clinical stage at Cleveland’s Case Western University followed by a clinical phase at USF Health and Tampa General. He estimates that it could be available for use on USF Health patients at TGH in three years.

“The plan is for me now to make a few trips to Cleveland, when it’s time for the animal experiments and to help facilitate that,” Dr. Bezerra said. “The next step will be testing for MRI compatibility and starting basic engineering work. A lot of bench and pre-clinical work still needs to take place before we can offer it to patients.”

Dr. Oliveira put it in perspective: “This is the holy grail of grants – where you go, as I said, from a bench concept and have a grant that will support the development of that product all the way to the bedside. It is not easy to do outside of the industry.”

The research also will be a natural fit for work that other physicians, such as Dr. Bibhu Mohanty, already are doing at USF and TGH to advance stroke care, Dr. Bezerra said. Dr. Mohanty, an associate professor in Internal Medicine at the College of Medicine, is an interventional cardiology specialist.

“This grant will complement our very active multidisciplinary neurocardiac program led by Dr. Mohanty in close collaboration with Neurology and Electrophysiology,” Dr. Bezerra said. “With the addition of this translation grant, USF/TGH will continue to be on the very cutting edge of stroke prevention.”

Story by Dave Scheiber for USF Health News.

Although stroke is a leading killer, experts say it demands more attention and funding.

On a Thursday night in mid-January, Dr. Rahul N. Mehra, a prominent Tampa psychiatrist, wasn’t feeling well and laid down on a couch in his south Tampa home. His wife Cathy was resting in the bedroom when she heard a loud thump and came out to investigate. She found her husband on the floor, disoriented.

“She looked at me and clearly realized that something wasn’t right,’’ Dr. Mehra said. “She asked me ‘who am I?’ and I wasn’t able to respond, so she immediately called the paramedics.’’

Dr. Rahul Mehra

Dr. Mehra is the CEO and Chief Physician Executive for the National Center for Performance Health (NCPH), a Tampa based health care company. NCPH creates and provides original and innovative resources intended to empower professional and amateur athletes of all ages. NCPH clients include large and small businesses, schools, colleges, universities and non-profit agencies. Dr. Mehra created a tool kit called Emotional Vaccines to address the effect of stress for individuals and families.

“Tampa General Hospital was just seven minutes away, so the paramedics got me there quick, and that saved my life.’’

But something else kept him motivated to live: “My spiritual belief pulled me through,’’ said the 60-year-old MD. “And my wife. If it wasn’t for her quick thinking, I might not be here today.’’

Dr. Rahul and Cathy Mehra

When the paramedics placed their patient into the ambulance, one of Dr. Mehra’s neighbors walked over to see what the commotion was about. She looked at him and held her hands together in prayer. In response, he gave her a thumbs up to say “I’m going to be ok.’’

And there was also COVID to consider: Both Dr. Mehra and Cathy had recently been vaccinated for COVID, but he still tested positive.

From there, it was up to a quickly assembled medical team at TGH to get Dr. Mehra back on his feet. Two days later, while in his hospital bed, Dr. Mehra suffered a second stroke.

Being a Saturday, some of the neurosurgery crew had to be called into work, led by Dr. W. Scott Burgin, Professor and Cerebrovascular Division Chief at the USF Health Morsani College of Medicine’s Department of Neurology and director of the Comprehensive Stroke Center at Tampa General Hospital.

“The nurse on shift found me unresponsive and alerted Dr. Burgin,’’ Dr. Mehra said.

The TGH team conducted a CAT scan and quickly identified the problem. “We converged on him within a matter of minutes, opened his artery back up and removed the clot in short order. Everyone worked as a finely tuned team,’’ Dr. Burgin said.

When news about Dr. Mehra’s failing health spread, three childhood friends flew to Tampa in a show of support. Each packed black clothing, “because they thought they were coming to a wake.’’

Rumors of Dr. Mehra’s passing were exaggerated and of course there was no funeral. In fact, he viewed what happened as a celebration of a renewed life.

“My recovery has been without any physical, sensory, or speech deficits,’’ he said. “The unparalleled recovery is the focus of the world-class care I received. Recall that three days after being found unconscious, paralyzed, blind and unable to speak in my hospital bed, I walked out of Tampa General’s Neuro ICU for discharge – not in a wheelchair but walking on my own strength.’’

Because a stroke cuts off blood and oxygen to the brain, it must be treated as an emergency. However, treatment is no easy task, Dr. Burgin said: A micro-catheter is inserted into the lower body and run upward to find the blockage in what may be a narrow blood vessel. “It’s like pushing a piece of string through the leg and up into the head.’’

More than 800,000 people a year in the United States suffer a stroke: enough to fill Tampa’s Raymond James Stadium 12 times over. Many of these people don’t know what hit them, and like Mehra, are in good health. This makes strokes difficult to predict and prevent. If not addressed quickly, a stroke can lead to brain hypoxia, permanent disability or death.

Stroke is among the top 10 leading causes of death in the United States:

• Heart disease
• Cancer
• Unintentional injuries
• Chronic lower respiratory disease
• Stroke and cerebrovascular diseases
• Alzheimer’s disease
• Diabetes
• Influenza and pneumonia

More on strokes: https://www.nhlbi.nih.gov/health/stroke

“Stroke is an incredibly under-resourced segment in medicine, even though it’s the No. 1 cause of disability and the No. 5 cause of death in the United States,’’ Dr. Burgin added. “We have heart centers everywhere, but not stroke centers.’’

For more about strokes and vascular neurology at USF, visit: https://health.usf.edu/care/neurology/services-specialties/stroke-vascularneurology

Story by Kurt Loft

A new device created at the University of South Florida – and including a cross-disciplinary team of experts from USF engineering, physical therapy and neurology – is showing early promise for helping correct the signature limp experienced by many stroke survivors.

Called the Gait Enhancing Mobile Shoe (GEMS), the shoe attachment is the result of multidisciplinary work and expertise in USF’s engineering, physical therapy, and neurology programs.

In addition to offering stroke patients good outcomes for improving their gait and balance, a preliminary study is showing the shoe also provides several advantages over a current stroke rehabilitation tool – the split-belt treadmill – including lower cost, greater convenience, and mobility.

“This is early in the process but we’re seeing the benefits we expected so it’s very promising,” said Kyle Reed, PhD, associate professor in the Department of Mechanical Engineering in the USF College of Engineering and principal investigator for the preliminary study on GEMS.

“We really want to help people who are limited in their walking ability to improve enough so they can return to the activities of their daily lives. The long-term hope is that this shoe attachment could be less expensive and safe enough that, once trained on how to use it, patients could take the GEMS home for therapy.”

Dr. Kim helps a patient try the GEMS shoe attachment.

Reed developed the GEMS shoe along with Seok Hun Kim, PT, PhD, associate professor in the School of Physical Therapy and Rehabilitation Sciences in the USF Health Morsani College of Medicine and co-principal investigator for the GEMS study. In 2010, Dr. Reed received funding from the National Institutes of Health to conduct a clinical trial of a small group of stroke survivors trying the GEMS; the study is not for severe stroke survivors, but mild to moderate stroke survivors.

The study also includes USF Health stroke expert David Z. Rose, MD, associate professor in the Department of Neurology in the USF Health Morsani College of Medicine, who said he sees the GEMS as a great potential option for stroke patients to improve their mobility.

“Many stroke patients are devastated that their ability to walk on their own can be so limited, even around their own homes,” Dr. Rose said. “Early data for the GEMS is very promising and the next phases of study will really help us see its true potential.”

Many stroke patients develop an asymmetric gait because of damage to their central nervous system, resulting in difficulty moving their affected leg – they can’t extend their foot backward enough, which prevents natural pushing off into the swing phase experienced in an unaffected walk.

Typical stroke rehabilitation to improve gait symmetry involves using a split-belt treadmill that offers two independent belts operating at different speeds to exaggerate the asymmetry of the patient’s gait.

But an odd yet natural thing happens when patients leave the treadmill – their brain returns to a fixed-floor state and they regress, with many finding it difficult to recreate the gait correction on solid ground, a regression that is called an after effect.

While generally successful for improving stroke patients’ gaits, the split-belt treadmill is expensive, requires a dedicated space to house and a qualified staff to monitor sessions and, because of after effect, can require more time for patients to master the correction, said Seok Hun Kim, PT, PhD, associate professor in the School of Physical Therapy and Rehabilitation Sciences in the USF Health Morsani College of Medicine.

“The GEMS allows movement across any safe surface, thus ‘rewiring’ the brain to learn the new compensation technique for everyday walking, not just for when they are on the treadmill,” Dr. Kim said.

“The GEMS is generally worn on the unaffected side, helping the patient use their affected side to compensate for the irregular footing.”

While early results of this preliminary study are showing strong support for a successful approach to improving the gait of stroke patients, more detailed study with more patients will be necessary. Dr. Kim said a full study, one that compares to the current approach with the split-belt treadmill, is critical before clinicians adjust their approach.

Dr. Kyle Reed demonstrates the GEMS shoe.

Story by Sarah Worth, photos and video by Sandra C. Roa, USF Communications

USF Health researcher Mack Wu, MD, studies what happens when the microvascular endothelial barrier controlling blood-tissue exchange is compromised during ischemia-reperfusion injury, a condition that can lead to irreversible tissue damage. He also investigates the molecular control of gut permeability, also known as “leaky gut,” in tissue injuries caused by trauma and severe burns.

His group’s work has broad implications for a variety of conditions including stroke, heart attack, thrombosis, sepsis, trauma or other inflammatory diseases associated with microvascular injury.

Mack Wu, MD, is a professor of surgery and molecular medicine at USF Health Morsani College of Medicine and a research physiologist at James A. Haley Veterans’ Hospital. On the monitor next to him are images of microvessels in the small intestine injected with fluorescent dye.

The closely connected endothelial cells lining the interior of blood vessel walls play a critical role in limiting the how much fluid, proteins and small molecules cross the wall of the tiny blood vessels, or microvessels. However when this protective endothelial barrier is damaged, excessive amounts of blood fluid, proteins and molecules leak outside the microvessels into nearby body tissue – a process known as microvascular hyperpermeability. If this breech of endothelial barrier is associated with a body-wide inflammatory response, it can trigger a chain of events leading to edema (swelling), shock from severe blood and fluid loss (hypovolemic shock), and ultimately multiple organ failure.

Pinpointing potential solutions for ischemia-reperfusion injury

Previous research by Dr. Wu’s laboratory and other groups discovered that ischemia-reperfusion injury can cause endothelial barrier damage leading to vascular hyperpermeability, or abnormally leaky blood vessels.

Ischemia-reperfusion injury is typically associated with conditions like organ transplantation, stroke, heart attack, or cardiopulmonary bypass where blood supply to a vital organ is temporarily cut off (ischemia), resulting in oxygen deprivation. For instance, a period of ischemia occurs while a donor organ is transported to a recipient in the operating room, or when a clot interrupts blood circulation to the brain. When blood supply is re-established with new blood returned to the previously oxygen-deprived area (reperfusion), tissue injury can worsen because the reperfusion itself causes inflammation and oxidative damage rather than restoring normal function. It its severest form, ischemia-reperfusion injury can result in multiple organ failure, or even death.

“I believe endothelial barrier injury is one of the key elements of ischemia-reperfusion injury, so my group is trying to find out which molecule is ultimately responsible for the endothelial barrier damage,” said Dr. Wu, a professor of surgery and molecular medicine at USF Health Morsani College of Medicine and a research physiologist at James A. Haley Veterans’ Hospital.

Dr. Wu with some members of his laboratory team. From left, Rebecca Eitnier, research assistant; Shimin Zhang, Department of Molecular Medicine graduate student; Ricci Haines, research associate; and Fang Wang, research assistant.

With the support of a $1.49-million, four-year R01 grant from the National Heart, Lung and Blood Institute, Dr. Wu’s team is zeroing in on a molecule known as focal adhesion kinase, or FAK, an enzyme that may play a role in weakening the microvascular endothelial barrier during ischemia-reperfusion injury.   Using cell models and a newly developed mouse model in which the endothelial-specific gene for FAK is knocked out, the USF researchers are testing whether selectively inhibiting FAK activity can rescue the endothelial barrier from such injury.

The work is critical because no FDA-approved treatment exists to prevent tissue damage following reperfusion. Identifying a new mechanism for the injury would provide potential targets for drug development, Dr. Wu said. So for instance, he said, after an initial stroke a new intravenously administered drug selectively targeting endothelial cells in the brain’s microvessels might stop further harmful swelling of the brain caused by stroke.

Defining molecular control of “leaky gut” in severe burn trauma

A second grant from the U.S. Department of Veterans Affairs funds Dr. Wu’s studies to define the underlying molecular mechanisms of leaky guts induced by traumatic injury associated with thermal (fire, scald or chemical) burns.  Massive burn trauma is a significant cause of injury and death in American soldiers. With a $960,000 VA Merit Award, Dr. Wu focuses on how intestinal epithelial barrier damage happens during severe burns, with the aim of developing targeted therapies to prevent posttraumatic complications.  In particular, he is working to determine the pathways by which the protein palmitoylation in gut epithelial cells are stimulated by burn injury.

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Epithelial cells line the interior of the small intestines, and after severe burn injury, this protective epithelial barrier commonly breaks down, causing bacteria and toxins to flow from the intestine into the circulating blood.  The result of this abnormal epithelial permeability, or “leaky gut,” can be deadly if sepsis ensues – a bacterial infection in the bloodstream sets up a body-wide inflammatory response leading to multiple organ failure.

While the role gut barrier failure plays in posttraumatic complications is well recognized, its cellular and molecular mechanisms remain poorly understood.  Currently, pushing IV fluids to help prevent hypovolemic shock and administering antibiotics and anti-inflammatories are the only therapies, mostly supportive, Dr. Wu said.

“More effective early therapeutic interventions to prevent leaky gut and systemic inflammatory response will be key to preventing sepsis,” he added, whether in soldiers with trauma or VA patients with inflammatory bowel diseases.

From industry to academia

Dr. Wu joined USF Health and the Haley VA Hospital in 2011.  He came from Sacramento, Calif, where he was an associate professor of surgery at the University of California at Davis School of Medicine and a research physiologist at Sacramento VA Medical Center.   Previously, Dr. Wu was a faculty member in the Department of Medical Physiology at Texas A&M University Health Science Center. He screened pharmaceutical compounds as a toxicologist in a biotechnology laboratory before joining Texas A&M, moving from industry to academia in 1995.

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Dr. Wu received his MD degree from Second Military Hospital in Shanghai, China, and conducted an internship at Shanghai Second Hospital.

One of his earliest and most highly cited studies, published in the American Journal of Physiology (1996), was first to report nitric oxide’s role in contributing to cardiovascular injury. The study showed an increase in nitric oxide induces vascular endothelial growth factor (VEGF) to promote leakage in tiny coronary veins.

Another more recent study in Shock (2012) provided direct evidence that thermal burn injury causes intestinal barrier disruption and inflammation characterized by intestinal mucosal permeability (leakage) and an infiltration of immune system cells known as neutrophils.

Something you may not know about Dr. Wu:

He loves deep-sea fishing. Dr. Wu has fished for sharks off the Golf coast of Texas, rockfish off the Pacific coast of California, and grouper off the west coast of Florida.

Dr. Wu is a member of the USF Health Heart Institute. His team’s work has broad implications for a variety of conditions including stroke, heart attack, thrombosis, sepsis, trauma or other inflammatory diseases associated with microvascular injury.

Photos by Eric Younghans, USF Health Communications and Marketing

University of South Florida  study shows research investment critical to prevent destabilizing economic impact

TAMPA, FL (March 29, 2017) — More Americans are living longer and surviving chronic conditions like heart disease and cancer. Ironically, this triumph is also leading to a drastic rise in neurological disorders, which disproportionately attack the elderly.

Clifton Gooch, MD, professor and chair of the Department of Neurology at the University of South Florida Morsani College of Medicine in Tampa, is the lead author of study that details the enormous cost of neurological diseases to the nation.  The study is reported in the Annals of Neurology, the official journal of the American Neurological Association and the Child Neurology Society.

Clifton Gooch, MD

Working with USF College of Public Health colleagues Etienne Pracht, PhD, and Amy Borenstein, PhD, Dr. Gooch looked at the nine most prevalent and costly diagnosed neurological disorders and found the annual cost is staggering, totaling nearly $800 billion. By 2030, $600 billion will be spent treating stroke and dementia alone.  In addition, low back pain, traumatic brain injury, migraine headache, epilepsy, multiple sclerosis, spinal cord injury and Parkinson’s disease emerged as the most common disorders posing a serious financial burden.

“Given these extraordinary and rapidly growing costs, a concrete strategy is urgently needed to reduce the burden of neurological disease,” he said.

In the paper, Dr. Gooch calls on the federal government to provide more NIH funding to speed the development of treatments and cures for diseases such as dementia and stroke, including therapies to delay, minimize and prevent them. He also proposes the creation of a more effective national database to track treatment successes and failures.

“The very future of the neurological sciences and the patients we serve is now at stake, and the welfare of generations yet to come hangs upon the success of our efforts.”

Dr. Gooch writes that the years of productivity lost in the 100 million Americans living with neurological and musculoskeletal disorders is more than any other category of disease.

-USF Health-
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and the USF Physicians Group. The University of South Florida, established in 1956 and located in Tampa, is a high-impact, global research university dedicated to student success. USF is ranked in the Top 30 nationally for research expenditures among public universities, according to the National Science Foundation. For more information, visit www.health.usf.edu

Media contact:
Tina Meketa, University Communications and Marketing
tmeketa@usf.edu or (813)955-2593

The founding director of the USF Health Heart Institute has a passion for innovation, translational medicine and entrepreneurship.

Samuel A. Wickline, MD, has parlayed his expertise in harnessing nanotechnology for molecular imaging and targeted treatments into an impressive $1-million portfolio of National Institutes of Health awards, multiple patents and four start-up biotechnology companies.

“We’ve developed nanostructures that can carry drugs or exist as therapeutic agents themselves against various types of inflammatory diseases, including, cancer, cardiovascular disease, arthritis and even infectious diseases like HIV,” said Dr. Wickline, who arrived at USF Health last month from the Washington University School of Medicine in St. Louis.

Dr. Wickline: “Innovation is not just about having a new idea, it’s about having a useful idea.”

 Dr. Wickline comments on how being a physician adds perspective to the science he conducts.

At Washington University, Dr. Wickline, a cardiologist, most recently was J. Russell Hornsby Professor in Biomedical Sciences and a professor of medicine with additional appointments in biomedical engineering, physics, and cell biology and physiology.

“I like the challenge of building things,” he said.

In St. Louis, he built a 29-year career as an accomplished physician-scientist keenly interested in translating basic science discoveries into practical applications to benefit patients. He served as chief of cardiology at Jewish Hospital, developed one of the first cardiac MRI training and research programs in the country, helped establish Washington University’s first graduate program in biomedical engineering, and led a university consortium that works with academic and industry partners to develop medical applications for nanotechnology.

At USF, there will be no shortage of challenging opportunities to build.

Building the USF Health Heart Institute

A major part of Dr. Wickline’s new job is helping to design, build and equip the Heart Institute. Most importantly, he will staff the state-of-the-art facility with a critical interdisciplinary mix of top biomedical scientists (including immunologists, molecular biologists, cell physiologists and genomics experts), who investigate the root causes of heart and vascular disease with the aim of finding new ways to detect, treat and prevent them. The Heart Institute will be co-located with new Morsani College of Medicine in downtown Tampa; construction on the combined facility is expected to begin later this year.

“I have been impressed by the energy and commitment here at the University of South Florida to invest substantial resources in a heart institute,” Dr. Wickline said. “I believe we have a lot to offer in terms of bench-to-bedside research that could solve some of the major cardiovascular problems” like atherosclerosis or heart failure.

“We want to put together a program that supplies the appropriate core facilities to attract the best and brightest researchers to this cardiovascular institute.”

Cardiovascular disease is the leading cause of death in the United States and worldwide, so exploring potential new treatment options is critical. One of the Heart Institute’s driving themes will be advancing concepts and findings that prove promising in the laboratory into projects commercialized for clinical use, Dr. Wickline said.

“Our goal is to make a difference in the lives of patients,” he said. “Innovation is not just about having a new idea, it’s about having a useful idea.”

Dr. Wickline also serves as associate dean for cardiovascular research and a professor of cardiovascular sciences at the Morsani College of Medicine. He holds the Tampa General Endowed Chair for Cardiovascular Research created last year with a gift from USF’s primary teaching hospital.

With Washington University colleague Hua Pan, PhD, a biomedical engineer and expert in molecular biology, Dr. Wickline is re-building his group at USF. Dr. Pan was recently recruited to USF as an assistant professor of medicine to continue her collaborations with Dr. Wickline.

 An example of Dr. Wickline’s group using nanotechnology to help combat atherosclerosis.

Dr. Wickline’s lab focuses on building nanoparticles to deliver drugs or other therapeutic agents to specific cell types, or targets.

Designing nanoparticles to “kill the messenger”

Dr. Wickline’s lab focuses on building nanoparticles – shaped like spheres or plates, but 10 to 50 times smaller than a red blood cell – to deliver drugs or other therapeutic agents through the bloodstream to specific cell types, or targets. These tiny carrier systems can effectively deliver a sizeable dosage directly to a targeted tissue, yet only require small amounts of the treatment in the circulation to reduce the risk of harmful side effects.

Some types of nanoparticles can carry image-enhancing agents that allow researchers to quantify where the illuminated particles travel, serving as beacons to specific molecules of interest, and enabling one to determine whether a therapeutic agent has penetrated its targeted site, Dr. Wickline said.

Dr. Wickline also is known for designing nanoparticles derived from a component of bee venom called melittin. While bee venom itself is toxic, Dr. Wickline’s laboratory has detoxified the molecule and modified its structure to produce a formula that allows the nanoparticles to carry small interfering (siRNA), also known as “silencing RNA,” or other types of synthetic DNA or RNA strand.

Among other functions, siRNA can be used to inhibit the genes that lead to the production of toxic proteins. Many in the nanotechnology research and development community are working to make siRNA treatment feasible as what Dr. Wickline calls “a message killer,” but the challenges have been daunting.

“The big challenge in the field of siRNA, and many companies have failed at this, is how to get the nanostructure to the cells so that the siRNA can do what it’s supposed – hit its target and kill the messenger — without being destroyed along the way, or having harmful side effects,” Dr. Wickline said. “We figured out how to engineer into a simple peptide all of the complex functionality that allows that to happen.”

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 Dr. Wickline comments on the underlying similarities between cardiovascular disease and cancer.

Different targets, same delivery vehicle

In a recent series of experiments in mice, Dr. Wickline and colleagues have shown that silencing RNA messages delivered by nanoparticle to a specific type of immune cell known as a macrophage – a “big eater” of fat – actually shrinks plaques that accumulate inside the walls of the arteries during atherosclerosis, one of the main causes of cardiovascular disease. The build-up of atherosclerotic plaques with fat-laden macrophages narrows, weakens and hardens arteries, eventually reducing the amount of oxygen-rich blood delivered to vital organs.

This type of plaque-inhibiting nanotherapy could be useful in aggressive forms of atherosclerosis where patients have intractable chest pain or after an acute heart attack or stroke to prevent a secondary cardiac event, Dr. Wickline said.

In another study, Washington University School of Medicine researchers investigated the potential of the siRNA nanoparticle designed by co-investigators Dr. Pan and Dr. Wickline in treating the inflammation that may lead to osteoarthritis, a degenerative joint disease that is a major cause of disability in the aging population. The nanoparticles — injected directly into injured joints in mice to suppress the activity of the molecule NF-κB — reduced local inflammation immediately following injury and reduced the destruction of cartilage. The findings were reported September 2016 in the Proceedings of the National Academy of Sciences.

Previously, Dr. Wickline said, the Washington University group had shown that nanoparticles delivered through the bloodstream inhibited inflammation in a mouse model of rheumatoid arthritis. And, another laboratory at the University of Kentucky is studying whether locally injected siRNA nanoparticles can quell the bacterial inflammation that can lead to a serious gum disease known as periodontitis. Other collaborating labs are using these nanoparticles in pancreatic, colon, and ovarian cancers with good effects.

“The specific targets in these cases may be different, but the nice thing about this kind of delivery system for RNA interference is that the delivery agent itself, the nanostructures, are the same,” Dr. Wickline said. “All we have to do is change out a little bit of the genetic material that targets the messages and we’re set up to go after another disease. So it’s completely modular and nontoxic.”

The St. Louis-based biotechnology company Trasir Therapeutics is developing these peptide-based nanocarriers for silencing RNA to treat diseases with multiple mechanisms of inflammation. Dr. Wickline co-founded the company in 2014 and continues to serve as its chief scientific officer.

Dr. Wickline with colleague Hua Pan, PhD, a biomedical engineer with expertise in molecular biology.

 Inhibiting chronic inflammation without getting rid of beneficial immune responses.

Calming the destructive cycle of inflammation

Dr. Wickline’s work is supported by several NIH RO1 grants, including one from the National Heart, Lung and Blood Institute to develop and test nanotherapies seeking to interrupt inflammatory signaling molecules and reduce the likelihood of thrombosis in acute cardiovascular syndromes.

In essence, Dr. Wickline said, he is interested in suppressing chronic inflammation, without disrupting the beneficial functions of surveillance by which the immune system recognizes and destroys invading pathogens or potential cancer cells.

“If you can inhibit the ongoing inflammation associated with (inappropriate) immune system response, you inhibit the positive feedback cycle of more inflammation, more plaques, more damage and more danger,” he said. “If you can cool off inflammation by using a message killer that says (to macrophages) ‘don’t come here, don’t eat fat, don’t make a blood clot’ – that’s what we think could be a game changer.”

Another NIH grant has funded collaborative work to develop an image-based nanoparticle that detects where in a compromised blood vessel too much blood clotting (hypercoagulation) occurs, and delivers potent anti-clotting agent only to that site. Formation of abnormal blood clots can trigger a heart attack when a clot blocks an artery that leads to heart muscle, or a stroke when a clot obstructs an artery supplying blood to the brain.

Because this site-specific nanotherapy targets only areas of active clotting, it may provide a safer, more effective approach against cardiac conditions like atrial fibrillation and acute heart attack than existing anticoagulant drugs such as warfarin and newer blood thinners like Xarelto® (rivaroxoban) or Eliquis® (apixiban), all which work systemically and come with raised risk for serious bleeding, Dr. Wickline said.

In a study published last year in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, Dr. Wickline and colleagues found that nanoparticles delivering a potent inhibitor of thrombin, a coagulant protein in blood that plays a role in inflammation, not only reduced clotting risk but also rapidly healed blood vessel endothelial barriers damaged during plaque growth.

The preclinical work showed the experimental treatment “is actually an anti-atherosclerotic drug as well as an anti-clotting drug, so there are many potential applications,” Dr. Wickline said.

Dr. Wickline received his MD degree from the University of Hawaii School of Medicine. He completed a residency in internal medicine, followed by clinical and research fellowships in cardiology at Barnes Hospital and Washington University, where he joined the medical school faculty in 1987.

He has authored more than 300 peer-reviewed papers and holds numerous U.S. patents. Dr. Wickline is a fellow of the American College of Cardiology and the American Heart Association, and a 2014 recipient of the Washington University Chancellor’s Award for Innovation and Entrepreneurship.

– Photos by Sandra C. Roa and Eric Younghans

Stroke’s long-term effects on blood-spinal cord barrier can lead to ‘an increasingly toxic environment’ in spinal cord and ‘significant input on disease pathology’

Tampa, Fla. (June 14, 2016) – A team of researchers at the University of South Florida investigating the short and long-term effects of ischemic stroke in a rodent model has found that stroke can cause long-term damage to the blood-spinal cord barrier (BSCB), creating a “toxic environment” in the spinal cord that might leave stroke survivors susceptible to motor dysfunction and disease pathology.

The paper describing their study was recently published online and will appear in an upcoming issue of Journal of Neuropathology and Experimental Neurology.

“This study, carried out using laboratory rats modeling stroke, demonstrated that ischemic stroke — in both its subacute and chronic stages — damages the BSCB in a variety of ways, creating a toxic environment in the spinal cord that can lead to further disability and exacerbate disease pathology,” said study lead author Svitlana Garbuzova-Davis, PhD, associate professor in USF’s Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair. “The aim of our study was to evaluate post-stroke BSCB condition that might lead to the development of more effective therapies for stroke survivors.”

Svitlana Garbuzova-Davis, PhD

The BSCB provides a specialized protective ‘microenvironment’ for neural cells in the spinal cord. Substantial vascular damage is a major pathologic feature of both subacute and chronic stroke caused by an extended period of microvascular permeability after the BSCB loses integrity. Damage to the BSCB, explained the researchers, plays a fundamental role in the development of several pathological conditions, including abnormal motor function.

The researchers, who evaluated the BSCB in test animals at seven and 30 days after stroke modeling, found that ischemic stroke damaged the gray and white matter in the cervical spinal cord on both sides of the spinal column, based on analysis of electron microscope images. Among the effects were damage to neural cells called ‘astrocytes,’ loss of motor neurons, reduced integrity of a tight junction protein between barrier cells, and swollen axons with damaged myelin in ascending and descending tracts connecting to the brain.

They also found stroke-associated ‘upregulation’ of Beclin-1 in endothelial cells composing the BSCB. Beclin-1, explained the researchers, helps induce autophagy, an activity associated with removal of various intracellular components. They also observed a decrease in LC3B, an essential autophagy protein, at a later stage post-stroke. These observations of Beclin-1 and LC3B suggest an impaired post-stroke autophagy process in spinal cord capillaries, inducing endothelial cell degeneration.

These stroke-related alterations in the cervical spinal cord indicate pervasive and long-lasting BSCB damage that would severely affect spinal cord function, wrote the researchers, adding that the widespread microvascular impairment in the gray and white matter of the cervical spinal cord aggravated motor neuron deterioration and had the potential to cause motor dysfunction.

“Because our investigations on the post-stroke microvascular alterations, including BSCB damage, have just begun, many questions remain,” said senior author Cesario Borlongan, PhD, professor and director of the USF Center of Excellence for Aging and Brain Repair. “Specifically, the protein expression responsible for endothelial cell degeneration and tight junction damage we identified in this study needs to be confirmed through further tests. Also, behavioral tests of motor function in post-stroke animals in correlation with BSCB damage are needed. These questions and others will be addressed in our future studies.”

Paul R. Sanberg, PhD, DSc, Distinguished University Professor, a co-author of the paper, concluded that “these novel data showing BSCB damage in subacute and chronic ischemic stroke may lead to development of new therapeutic approaches for patients with ischemic cerebral infarction.”

Article citation:
Blood-Spinal Cord Barrier Alterations in Subacute and Chronic Stages of a Rat Model of Focal Cerebral Ischemia. Svitlana Garbuzova-Davis; Edward Haller; Naoki Tajiri; Avery Thomson; Jennifer Barretta; Stephanie N. Williams; Eithan D. Haim; Hua Qin; Aric Frisina-Deyo; Jerry V. Abraham; Paul R. Sanberg; Harry Van Loveren; Cesario V. Borlongan. Journal of Neuropathology & Experimental Neurology 2016; doi: 10.1093/jnen/nlw040.

-USF Health-
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and the USF Physicians Group. The University of South Florida is a Top 50 research university in total research expenditures among both public and private institutions nationwide, according to the National Science Foundation. For more information, visit www.health.usf.edu

– News release by Randy Fillmore, USF Communications and Marketing

Heart disease and stroke impact so many families across the United States, including our own families here at USF Health.

The American Heart Association is holding its annual Heart Walk to raise funds and awareness for heart disease and stroke, and USF Health faculty, staff and students are gearing up to participate.

The annual event draws thousands from across the Tampa Bay area and is one of nearly 340 events held across the country each year. In total, the national AHA Heart Walk events include more than 1 million walkers.

USF Health faculty, staff and students participate in the local event – details below – by forming teams, making direct donations, sponsoring teams and walking themselves as ways to help raise funds for the American Heart Association and awareness for heart disease and stroke.

While many walk for the cause in general, a large number walk for someone they know battling heart disease or living with stroke. Many are walking in memory of loved ones who have been lost to these diseases. Heart disease and stroke continue to top the list at #1 and #5 for killer diseases in the United States.

USF Health takes active roles in helping AHA’s search for cures, said Phillip J. Marty, PhD, vice president for USF Health Research.

“A foundation of science is what will help find new therapies, treatments and procedures for ending heart disease and stroke,” he said. “We have many promising scientists doing promising research that is laying the groundwork for advances.”

USF Health faculty currently have 11 AHA-funded research awards totaling nearly a million dollars aiming toward the solid science that could lead to cures.

“Much of the work we do at USF falls into the category of translational research, in which basic science researchers work with our clinical researchers to test and translate their work into treatments, cures and preventive measures,” Dr. Marty said. “These collaborative research approaches will ultimately help reduce, and even eradicate, forms of cardiovascular disease and stroke in future generations.”

Click here to register or contribute today!  Participation is not limited to employees and students, so please encourage your family and friends to join a USF team.

And check out a great video for this year’s Heart Walk!

Details:

AHA Heart Walk – Tampa

Saturday, Nov. 7

Raymond James Stadium, 4201 N. Dale Mabry Hwy., Tampa, FL 33607

Festivities Begin at 8:00 a.m. and the walk kicks off at 9:00 a.m.  Plan to arrive early for parking, which is free in the general parking lot south of Raymond James Stadium between Dale Mabry and Himes. The walk route will be 3.2 miles with a one-mile route option.