Leading in Research
Dr. Mack Wu studies molecular control of ischemia-reperfusion injury, leaky gut
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.
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.
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.
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.
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.
Photos by Eric Younghans, USF Health Communications and Marketing
USF researcher studies irregular cardiac electrical signals
Seeking to understand how the heart short circuits, Sami Noujaim looks for new drugs to fix atrial fibrillation
Within the last three years, USF biomedical scientist Sami Noujaim, PhD, lost his older brother to sudden cardiac death and his 80-year-old father was diagnosed with atrial fibrillation.
The experiences gave Dr. Noujaim a new appreciation for his research on understanding how normal and abnormal electrical impulses are generated in the heart. The Cardiac Electrophysiology Research Laboratory he directs focuses on finding more effective drugs to treat atrial fibrillation, the most common irregular heart rhythm and a condition for which prevalence rises markedly after age 65.
“When life throws something like that at you, the work you do takes on a more personal tone, a sense of mission. I realized that neither myself nor my loved ones are immune from the cardiovascular diseases I’m studying,” said Dr. Noujaim, an assistant professor in the Morsani College of Medicine’s Department of Molecular Pharmacology and Physiology. “We are all at risk.”
Searching For Noninvasive Solutions To Atrial Fibrillation
Atrial fibrillation is a problem with the cardiac electrical circuitry that controls the rate and rhythm of the heartbeat. The condition affects about 9 percent of the U.S. population age 65 or older, according to the Centers for Disease Control and Prevention, and can lead to potentially deadly complications such as stroke and heart failure. While signs of atrial fibrillation may include heart palpitations, fatigue, lightheadedness, dizziness and shortness of breath, some people experience no noticeable symptoms.
Treatment and management options include lifestyle changes, medications to help control heart rate and rhythm and reduce the risk of blood clots, controlled electrical shock (cardioversion to reset heart rhythm), invasive procedures (catheter ablation) and surgical implantation of pacemakers. However, a major challenge is that atrial fibrillation frequently recurs after normal heart rhythm (sinus rhythm) is restored.
“The existing treatments can be good, but there is a lot of room for improvement, so we are focusing on contributing to noninvasive treatment options,” Dr. Noujaim said. “If we could help physicians get patients with atrial fibrillation to long-term normal sinus rhythm, and perhaps increase the ability to take them off blood thinners, it would be a significant improvement.”
The significance of investigating the relationship between aging and atrial fibrillation.
Designing A “Perfect Plug” Using An Antimalarial Drug Model
“Right now, we are trying to design a perfect plug using the antimalarial drug chloroquine as a model,” Dr. Noujaim said, “We have evidence that if we block that specific type of potassium channels we will be able to stop atrial fibrillation or at least reduce its occurrence.”
Earlier work by Dr. Noujaim and others, including a study reported in the journal FASEB, demonstrated that the antimalarial drug chloroquine was effective in blocking the GIRK potassium channels and suggested a new path for discovering antiarrhythmic drugs.
Dr. Noujaim continues using cellular and animal models to pinpoint how and where the chloroquine molecule interacts with the potassium channel – with the aim of discovering a “plug” that works even better than the antimalarial drug. At the same time, he has reached out to USF Health Department of Cardiovascular Sciences to begin applying the laboratory findings to the clinic.
Working with cardiologists Bengt Herweg, MD, and Dany Sayad, MD, Dr. Noujaim recently gained approval for a pilot study to enroll 40 adults without heart damage whose atrial fibrillation has persisted more than one week and less one year. The team will test the effectiveness of chloroquine in restoring and maintaining normal heart rhythm in patients with atrial fibrillation.
Dr. Noujaim came to USF in 2015 from the Molecular Cardiology Research Institute at Tufts University School of Medicine. He received his PhD in pharmacology, with distinction, from SUNY Upstate Medical University in Syracuse, NY, followed by a year of postdoctoral training there. He then completed a three-year postdoctoral fellowship, supported by the American Heart Association, and the National Institutes of Health, at the Center for Arrhythmia Research, University of Michigan, in Ann Arbor, MI.
Dr. Noujaim said he was attracted to USF by the opportunity to be part of an emerging preeminent university committed to establishing a cardiovascular institute bridging top biomedical research and clinical care.
“The opportunities that the University of South Florida is providing for scientists are equal or greater than those at any other major academic medical center,” he said. “It was also striking to me that, in a place the size of USF, the USF Health leadership is so actively engaged in research, with their own laboratories and grants. That’s not what you would see in a lot of places, and as a biomedical scientist it makes me feel that the leadership here really values research.”
- Born in Lebanon, he moved to the United States after graduating from high school.
- He routinely swims laps in an indoor pool.
- He enjoys experimenting with cooking, specializing in inventing new dishes by combining ingredients he finds in his refrigerator. “I’ve discovered by trial and error that no matter how bad what I cook really is, adding a tablespoon of soy sauce makes it alright,” he said.
- His first scientific experiment as a college student volunteering in Boston’s Beth Israel Deaconess Medical Center laboratory was unforgettable. He fainted while his blood was being drawn so he could use it to help study blood platelet activation and aggregation. Click on video below to find out more.
- – Written by Anne Delotto Baier, Photos by Sandra C. Roa and Eric Younghans
Pioneering nanotechnology research has applications for cardiovascular diseases
June 15, 2017
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.
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.
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.”
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.
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.
Some things you may not know about Dr. Wickline
- His first scientific experiment was conducted at age 21, before entering medical school, when he worked in a research laboratory in Hawaii run by a cardiovascular surgeon interested in techniques to best support the heart during cardiopulmonary bypass surgery. Dr. Wickline figured out why one particular way of perfusing blood through the heart pump machine could dangerously compromise oxygenated blood flow to the brain. The results were published in the Annals of Thoracic Surgery. One of Dr. Wickline’s first studies in medical school, published in the prestigious journal Circulation, described a method for determining the size of a heart attack by recording electrical signals, called vector cardiograms.
- He grew up in St. Petersburg, Fla., and did some trick water skiing as a teen. “I learned how to ski backwards.” After being “landlocked” in Missouri for 37 years following medical school in Hawaii, he said he’s glad for the opportunity to get back to get back to the beach and water sports.
- He likes to play the ukulele.
– Story by Anne Delotto Baier, photos and video by Sandra C. Roa