Trainees will benefit from USF Health’s increase in nationally recognized faculty with research expertise in blood vessel inflammation linked to heart, lung and other diseases

TAMPA, Fla (Feb. 3, 2022) — The University of South Florida recently received a highly competitive National Institutes of Health (NIH) Institutional Training Grant (Award Number T32HL160529), boosting the USF Health Morsani College of Medicine’s (MCOM) capacity to prepare the next generation of scientists in an emerging area of research applicable to many major diseases.

The NIH’s National, Heart, Lung, and Blood Institute awarded MCOM total expected funds of $1.35 million over the next five years to support the comprehensive training of pre- and postdoctoral scientists focused on research in vascular inflammation and injury. Trainees will be selected from PhD candidates and graduates, as well as MD graduates in residency or fellowship programs related to cardiovascular sciences. They will receive stipends and financial support for attending scientific conferences.

The USF Health Morsani College of Medicine’s new NHLBI Institutional Training Grant for research in vascular inflammation and injury is directed by Sarah Yuan, MD, PhD (center), professor and chair of Molecular Pharmacology and Physiology (MPP).  Joining Dr. Yuan are core MPP members of the T32 grant team, from left to right: Victoria Mothershed, the program’s administrative manager; Thomas Taylor-Clark, PhD, the program’s associate director; and Jerome Breslin, PhD, who designs and oversees the program’s curriculum. — Photo by Allison Long, USF Health Communications

“This is the first NIH T32 institutional training award obtained by USF’s college of medicine in the last 20 years,” said program director Sarah Yuan, MD, PhD, professor and chair of the Department of Molecular Pharmacology and Physiology. “It represents a critical step in raising our national prominence in training the next generation of translational researchers.”

Translational research is the process of efficiently moving scientific discoveries made in the laboratory into the clinic, hospital, or community to treat patients and improve health.

“Our goal is to prepare these trainees with the strong knowledge, skills and vision for leading independent research that will decipher complex cellular and molecular mechanisms and develop new diagnostic and therapeutic targets for cardiovascular disease and other conditions affected by inflammation,” said Dr. Yuan, who holds the USF Health Deriso Endowed Chair in Cardiovascular Research.

Inflammation commonly underlies the onset and progression of various diseases or injuries in multiple organs, including the heart, brain, lung, kidney, gut, and placenta. Recently, Dr. Yuan noted, this includes the discovery that vascular inflammation in response to coronavirus infection is a leading cause of severe illness and death in COVID patients.

A better understanding of the physiological processes contributing to vascular inflammation can lead to more precise and much-needed ways to diagnose, treat, and possibly prevent its harmful effects,

The new training program takes advantage of the substantial number of NIH-funded researchers recruited to MCOM under the leadership of Charles J. Lockwood, MD, senior vice president for USF Health and dean of MCOM. Many of these nationally preeminent faculty hires are experts in inflammation research and the vascular biology associated with heart, lung, neurodegenerative, or other diseases. Investment in new and renovated laboratories, and research facilities with shared, highly specialized equipment has risen along with the influx of new investigators.

Up to 25 NIH-funded faculty mentors across seven MCOM departments (Molecular Pharmacology and Physiology, Internal Medicine, Surgery, Obstetrics and Gynecology, Pediatrics, Pathology and Medical Engineering), including those affiliated with the USF Health Heart Institute, the USF Health Neuroscience Institute, and several other research centers, will mentor top students recruited to the T32 program.

“Our commitment to building the research infrastructure, expertise and curriculum needed to attract the highest caliber of faculty and academically talented students will not waver,” Dr. Lockwood said. “This new institutional training award is a tremendous addition to our growing research portfolio, one that helps feed a pipeline of diverse young scientists driven to transform meaningful discoveries into best-practice patient care. They will be well prepared to understand and help solve complex problems beyond the scope of individual disciplines or laboratories.”

The latest scientific equipment and imaging techniques will help trainees investigating the complex cellular and molecular processes contributing to inflammatory changes in and surrounding the tiniest blood vessels.  — Photo by Allison Long, USF Health Communications

The program’s curriculum is composed of rigorous courses and workshops to build competency in critical thinking and communication, an intensive hands-on research experience, and a personalized career development plan. Trainees will have access to the latest technologies, including viable human organ models to study the effects of inflammatory disease and its treatment, and high-resolution imaging techniques to see changes in blood flow, cells, proteins, and other structures within and outside the tiniest vessels.

Program director Dr. Yuan is joined by several core members of MCOM Molecular Pharmacology and Physiology, including Thomas Taylor-Clark, PhD, the program’s associate director; Jerome Breslin, PhD, who designs and oversees the program’s curriculum; and Victoria Mothershed, the program’s administrative manager.

“It took the support of leadership, dedicated teamwork, and perseverance to get here,” Dr. Yuan said. “We’re thrilled to receive this institutional award and want it to be catalyst for more such programs cultivating leaders in biomedical and translational science.”

First-in-human study of diffuse optical tomography during rTMS suggests treatment target or parameters may need adjusting to benefit more patients with severe depression

TAMPA, Fla. (May 4, 2021) — Repetitive transcranial magnetic stimulation, or rTMS, was FDA approved in 2008 as a safe and effective noninvasive treatment for severe depression resistant to antidepressant medications. A small coil positioned near the scalp generates repetitive, pulsed magnetic waves that pass through the skull and stimulate brain cells to relieve symptoms of depression. The procedure has few side effects and is typically prescribed as an alternative or supplemental therapy when multiple antidepressant medications and/or psychotherapy do not work.

Despite increased use of rTMS in psychiatry, the rates at which patients respond to therapy and experience remission of often-disabling symptoms have been modest at best.

Now, for the first time, a team of USF Health psychiatrists and University of South Florida biomedical engineers applied an emerging functional neuroimaging technology, known as diffuse optical tomography (DOT), to better understand how rTMS works so they can begin to improve the technique’s effectiveness in treating depression. DOT uses near-infrared light waves and sophisticated algorithms (computer instructions) to produce three-dimensional images of soft tissue, including brain tissue.

Shixie “Max” Jiang, MD, (above) a third-year psychiatry resident in the USF Health Morsani College of Medicine, and his father Huabei Jiang, PhD, (below) a professor in the Department of Medical Engineering, collaborated on the study.

Comparing depressed and healthy individuals, the USF researchers demonstrated that this newer optical imaging technique can safely and reliably measure changes in brain activity induced during rTMS in a targeted region of the brain implicated in mood regulation. Their findings were published April 1 in the Nature journal Scientific Reports.

“This study is a good example of how collaboration between disciplines can advance our overall understanding of how a treatment like TMS works,” said study lead author Shixie Jiang, MD, a third-year psychiatry resident at the USF Health Morsani College of Medicine. “We want to use what we learned from the application of the diffuse optical tomography device to optimize TMS, so that the treatments become more personalized and lead to more remission of depression.”

DOT has been used clinically for imaging epilepsy, breast cancer, and osteoarthritis and to visualize activation of cortical brain regions, but the USF team is the first to introduce the technology to psychiatry to study brain stimulation with TMS.

“Diffuse optical tomography is really the only modality that can image brain function at the same time that TMS is administered,” said study principal investigator Huabei Jiang, PhD, a professor in the Department of Medical Engineering and father of Shixie Jiang. The DOT imaging system used for USF’s collaborative study was custom built in his laboratory at the USF College of Engineering.

A small coil positioned near the scalp generates repetitive, pulsed magnetic waves that pass through the skull and stimulate brain cells (neurons) to relieve symptoms of depression. A typical rTMS session lasts 30 to 60 minutes and does not require anesthesia.

The researchers point to three main reasons why TMS likely has not lived up to its full potential in treating major depression: nonoptimized brain stimulation targeting; unclear treatment parameters (i.e., rTMS dose, magnetic pulse patterns and frequencies, rest periods between stimulation intervals), and incomplete knowledge of how nerve cells in the brain respond physiologically to the procedure.

Portable, less expensive, and less confining than some other neuroimaging equipment like MRIs, DOT still renders relatively high-resolution, localized 3D images. More importantly, Dr. Huabei Jiang said, DOT can be used during TMS without interfering with treatment’s magnetic pulses and without compromising the images and other data generated.

DOT relies on the fact that higher levels of oxygenated blood correlate with more brain activity and increased cerebral blood flow, and lower levels indicate less activity and blood flow. Certain neuroimaging studies have also revealed that depressed people display abnormally low brain activity in the prefrontal cortex, a brain region associated with emotional responses and mood regulation.

By measuring changes in near-infrared light, DOT detects changes in brain activity and, secondarily, changes in blood volume (flow) that might be triggering activation in the prefrontal cortex. In particular, the device can monitor altered levels of oxygenated, deoxygenated, and total hemoglobin, a protein in red blood cells carrying oxygen to tissues.

Above: Cross-sectional 3D images of brain activity (red to yellow) in healthy volunteers, reconstructed from total hemoglobin data collected by diffuse optical tomography. Data from the brain’s right side only was acquired during a 30-second period of rTMS. The bronze coil symbol represents stimulation of the left side. Below: 3D images using the same rTMS protocol in depressed participants indicate minimal or no brain activity. | Photos courtesy of Shixie Jiang, MD

The USF study analyzed data collected from 13 adults (7 depressed and 6 healthy controls) who underwent DOT imaging simultaneously with rTMS at the USF Health outpatient psychiatry clinic. Applying the standard rTMS protocol, the treatment was aimed at the brain’s left dorsolateral prefrontal cortex – the region most targeted for depression.

The researchers found that the depressed patients had significantly less brain activation in response to rTMS than the healthy study participants. Furthermore, peak brain activation took longer to reach in the depressed group, compared to the healthy control group.

This delayed, less robust activation suggests that rTMS as currently administered under FDA guidelines may not be adequate for some patients with severe depression, Dr. Shixie Jiang said. The dose and timing of treatment may need to be adjusted for patients who exhibit weakened responses to brain stimulation at baseline (initial treatment), he added.

Larger clinical trials are needed to validate the USF preliminary study results, as well as to develop ideal treatment parameters and identify other dysfunctional regions in the depression-affected brain that may benefit from targeted stimulation.

“More work is needed,” Dr. Shixie Jiang said, “but advances in neuroimaging with new approaches like diffuse optical tomography hold great promise for helping us improve rTMS and depression outcomes.”

The DOT device is connected to an individual’s scalp by fiber-optic cables comprised of source-detector sensors held in place by a modified EEG cap. The paired sensors both transmit the near-infrared light and convert light dispersed from brain tissue into the signals needed to reconstruct 3D brain images. | Photo courtesy of Huabei Jiang, PhD

New USF Health research on endothelial-derived microvesicles, using models of sepsis, may be useful for better diagnosis and treatment of inflammatory or infectious diseases

A new preclinical study by the University of South Florida Health (USF Health) Morsani College of Medicine sheds light on how tiny bubble-like particles flowing in the blood can serve as diagnostic markers for certain diseases while also contributing to disease progression.

Microvesicles (green) interacting with target endothelial cells (nuclei stained blue) to increase both stress fiber formation (red) and activation of cellular contraction proteins (yellow). The interaction contributes to greater vascular wall barrier permeability (leakage). Image courtesy of Victor Chatterjee (University of South Florida), originally published by Oxford University Press, Cardiovascular Research, https://doi.org/10.1093/cvr/cvz238

Cells lining the inner surface of blood vessels, called endothelial cells, have the ability to package and release microscopic vesicles (0.1 to 1 micrometer in diameter) into the blood circulation. These microvesicles carry unique cargo of molecules under different health or disease conditions; thus, by identifying their specific cargo content or molecular signature, doctors can better diagnose the nature and extent of a medical problem.

Researchers in the laboratory of Sarah Yuan, MD, PhD, at the USF Health Department of Molecular Pharmacology and Physiology, discovered that endothelial cells produce microvesicles containing a high level of c-Src protein during sepsis, a life-threatening condition that causes systemic inflammation and multiple organ failure. Their study, conducted using cell cultures and an animal model of sepsis, was recently reported in Cardiovascular Research, a highly rated journal sponsored by the European Society of Cardiology.

Most intriguingly, the researchers found that in addition to providing a unique marker that signifies the status of inflammation in blood vessels, these c-Src enriched microvesicles play an active role in causing vascular wall injury and barrier leakage.

Victor Chatterjee, MD, PhD, a postdoctoral fellow in the Department of Molecular Pharmacology and Physiology, was the paper’s first author. He works in the laboratory of departmental chair Sarah Yuan, MD, PhD. | Photo by Allison Long, USF Health Communications and Marketing

“Microvesicles produced by inflamed endothelial cells circulate in the blood and target healthy barrier cells by unloading their bioactive cargo into receiving cells. They ‘tell’ the receiving cells to change behavior, leading to an increased permeability of the barrier,” said first author Victor Chatterjee, MD, PhD, a postdoctoral fellow working in Dr. Yuan’s lab.

Like the breech of a protective levy, increased permeability of the endothelial barrier allows blood fluids and proteins to leak through the blood vessel wall into surrounding tissues. Because this leak process underlies sepsis, traumatic injury, atherosclerosis, cancer, and several types of inflammatory or immunological disorders, the authors suggest that endothelial-derived microvesicles may have potential applications in developing new molecular markers or therapeutic targets for better diagnosis and treatment of these diseases.

This paper also reports an in-depth analysis of the molecular mechanisms underlying vascular leakage caused by endothelial derived microvesicles.

A key finding is that the circulating microparticles are highly interactive. They bind to the membrane of targeted endothelial cells and get inside these cells, where they unload c-Src cargo to turn on the signal for cell contraction and cell-to-cell junction opening. Since junctions are critical structures that “glue” neighboring cells together to form the vascular wall barrier, opening them results in blood leakage.

Dr. Yuan, a member of the USF Health Heart Institute, was senior author of the NIH-supported study published in Cardiovascular Research.

In an effort to translate their benchwork to bedside care, the USF Health researchers plan to use blood samples from human patients to determine if and how the molecular signature of microvesicles change over time or correlate with disease severity, Dr. Chatterjee said.  A better understanding of how these tiny cargo carriers function in the human disease process could help guide physicians in better managing infectious or inflammatory diseases, he said.

The senior author of the Cardiovascular Research paper is Dr. Yuan, professor and department chair, who holds the USF Health Deriso Endowed Chair in Cardiovascular Disease. Dr. Yuan’s research has been supported by the National Institutes of Health: National Heart, Lung, and Blood Institute, and National Institute of General Medical Sciences.

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USF Health preclinical study tests several formulations of chitosan-enriched siRNA nanoparticles intended to improve gene therapy targeting neurodegenerative diseases

Neurologist Juan Sanchez-Ramos, MD, PhD, director of USF Health’s HDSA Huntington’s Disease Center of Excellence, examines patient and clinical trial participant Brittany Bosson.

Huntington’s disease (HD) is a hereditary brain disease that typically strikes adults in the prime of life – leading to progressive deterioration of movement, mood and thinking. While some drugs temporarily alleviate symptoms, currently no therapies prevent, slow or stop the course of HD.

Juan Sanchez-Ramos, MD, PhD, the Helen Ellis Professor of Neurology and director of  the HDSA Huntington’s Disease Center of Excellence, University of South Florida Health (USF Health), sees firsthand how this devastating illness – sometimes described as a mix of Parkinson’s disease, ALS and Alzheimer’s disease — affects patients and their families.  For the last several years, even as he leads clinical trials evaluating potential new drugs, the physician-scientist has worked with a mouse model of HD to develop and test a nanoparticle system that can precisely deliver gene therapy from the nose to areas of the brain most affected by HD.

He is closer than ever before to a viable noninvasive treatment – one that could be administered by nasal spray or drops, rather than spinal puncture or direct injection into the brain.

In a preclinical study published Oct. 27 in Nanomedicine: Nanotechnology, Biology and Medicine, senior author Dr. Sanchez-Ramos and colleagues build on their earlier findings demonstrating that chitosan-enriched, manganese-coated nanoparticles loaded with small interfering RNA (siRNA) could be successfully delivered by nose drops to targeted parts of the brain affected by HD.  In a Huntington’s disease mouse model the nanoparticles reduced expression of the mutated HTT gene that causes HD by at least 50% in four regions: the olfactory bulb, striatum, hippocampus and cortex. The defective HTT gene leads to production of a toxic form of protein, known as the huntingtin protein. In essence, this new treatment silences the genetic message “telling” a cell to generate more huntingtin proteins. To ultimately benefit patients, the abnormal protein production must be reduced enough to block or slow the dysfunction and eventual loss of nerve cells accounting for clinical symptoms.

“Our nose-to-brain approach for delivery of gene therapies is non-invasive, safe and effective,” said Dr. Sanchez-Ramos, a co-inventor of the novel anti-HTT siRNA nanoparticle delivery system patented by USF.

Searching for ways to optimize HD gene silencing

For the latest study, reported in Nanomedicine, Dr. Sanchez-Ramos collaborated with researchers from the USF Health Department of Neurology and the University of Massachusetts Medical School’s RNA Therapeutics Institute.  Seeking to optimize HD gene silencing when the siRNA is delivered by a nasal route, the team tested different formulations and sizes of the nanoparticles in a mouse model expressing the human HD gene. Among their findings:

— Four different versions of the nanoparticles tested lowered HD gene expression in the brain by 50%. However, lowering levels of the toxic huntingtin protein in brain tissue took longer, with the highest reduction of the protein (53%) seen in the olfactory bulb at the base of the brain and the lowest (38%) in the cerebral cortex, the brain’s outer layer. Also, simply administering “naked” siRNA through the nose (without the protective chitosan encasement) did little to reduce HD gene expression even though previous research has shown similar naked siRNA injected directly into the brain was highly effective.

— Enclosing the siRNA in chitosan protected the silencing RNA from being prematurely degraded “en route” to its HD brain targets. The compound chitosan is derived from the hard outer skeleton of shellfish or the external skeleton of insects. Encapsulating siRNA into a chitosan nanoparticle allowed the silencing RNA to be enriched to higher doses without damaging the molecule, resulting in significant reduction in HD gene expression, the researchers report.

— Increasing the number siRNA nanoparticles within a defined dose of nose drops is a key to improving therapeutic potential. “The ability to fabricate concentrated NP (nanoparticle) preparations without damaging siRNA content is a critical factor for successful intranasal delivery of gene silencing agents,” the researchers concluded.

A major challenge of gene therapy for HD and other neurodegenerative diseases has been getting the molecules intended to replace a missing gene or suppress an overactive gene past the blood-brain barrier, a kind of defensive wall that selectively filters which molecules can enter the brain from circulating blood.

But over the last several years, research progressed in overcoming this barrier and promising laboratory findings set the stage for clinical trials in patients with HD.

For example, led by Dr. Sanchez-Ramos, USF Health is the only Florida site participating in the Roche-sponsored GENERATION HD1 Study. This pivotal phase 3 international clinical trial is testing whether a huntingtin-lowering, antisense oligonucleotide drug can halt underlying pathology of the disease enough to improve symptoms in adult patients. The injectable drug, administered directly into the cerebral-spinal fluid, successfully bypasses the blood-brain barrier and stopped disease progression in laboratory models. However, the investigational drug must be administered every two months by lumbar puncture at the clinic.

The normal huntingtin gene contains a DNA alphabet that repeats the letters C-A-G as many as 26 times, but people who develop Huntington’s disease have an excessive number of these consecutive C-A-G triplet repeats — greater than 39.| Graphic by Sandra C. Roa

Working toward a simpler, noninvasive treatment

With a chronic illness that gradually encompasses the entire central nervous system, like HD, even minimally-invasive injections with fine needles or infusions may pose risks of infection or other complications associated with neurosurgical procedures, Dr. Sanchez-Ramos said. So, he continues to work toward a noninvasive nose-to-brain treatment that would be simpler to repeat and well-tolerated by patients over their lifetime.

Dr. Sanchez-Ramos says the idea for incorporating nontoxic amounts of manganese chelate into the chitosan-based nanoparticles to help gene therapy delivery was sparked by early studies investigating how welders exposed to high levels of neurotoxic manganese oxide from welding fumes developed Parkinson’s disease symptoms.  It turns out that the olfactory nerve has an affinity for the chemical manganese.

“Manganese is good at guiding our nanoparticles from the nasal passages to the olfactory nerves and transporting the particles directly to structures deep in the brain… Realizing that was one of our biggest breakthroughs,” he said.  Manganese also permits the nanoparticles to be visualized by MRI imaging, so that their distribution and accumulation in different regions of brain can be tracked.

The nose-to-brain method of delivering the manganese-containing siRNA nanoparticles needs to be tested in a larger-brain animal model before moving to human trials.

The USF Health study was supported by a grant from the National Institute of Health’s National Institute of Neurological Disorders and Stroke.

As his preclinical research on nose-to-brain delivery of gene therapy for Huntington’s disease progresses, Dr. Sanchez-Ramos serves as Florida principal investigator for a worldwide clinical trial testing an injectable drug designed to slow the progression of Huntington’s disease.

-Photos by Allison Long, USF Health Communications and Marketing

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

Tampa, FL (Dec. 20, 2016) — Samuel A. Wickline, MD, has joined the USF Health Morsani College of Medicine to lead a state-of-the-art heart institute that will integrate biomedical research with advanced clinical care to find new ways to detect, treat and prevent cardiovascular diseases and improve the heart health of the Tampa Bay community.

Dr. Wickline, a cardiologist, came to USF earlier this month from Washington University School of Medicine in St. Louis, where he was the J. Russell Hornsby Professor in Biomedical Sciences and a professor of medicine with additional appointments in biomedical engineering, physics, and cell biology and physiology.

As the first director of the USF Health Heart Institute, he will be instrumental in helping design, build, equip and staff the Heart Institute to be co-located with the new Morsani College of Medicine in downtown Tampa. Among his responsibilities will be the recruitment of a critical mass of cardiovascular scientists at the forefront of interdisciplinary biomedical research to define the root causes of heart and vascular disease leading to new diagnostics and treatments.

Samuel Wickline, MD, a cardiologist, is the USF Health Heart Institute’s first director. – Photo by Sandra C. Roa

Dr. Stephen Liggett, vice dean for research at the Morsani College of Medicine, and Dr. Arthur Labovitz, chair of the college’s Department of Cardiovascular Sciences, served as co-directors of the Heart Institute during its early planning and design phase.

“With a foundation firmly in place, we look forward to Dr. Wickline’s leadership in helping us build a world-class cardiovascular clinical and research program positioned to accelerate USF’s path to preeminence,” said Dr. Charles J. Lockwood, senior vice president for USF Health and dean of the Morsani College of Medicine.

Dr. Wickline will fill the Tampa General Hospital Endowed Chair for Cardiovascular Research, which was created earlier this year with a gift from USF’s primary teaching hospital.  He also holds appointments as associate dean for cardiovascular research and a professor of cardiovascular sciences at the Morsani College of Medicine.

“Heart disease is the number one killer of people in the world and the United States, and there are still innumerable problems to solve,” said Dr. Wickline, who is in the process of setting up his own laboratory at USF. “I have been impressed by the energy and commitment here at the University of South Florida to invest substantial resources in a heart institute… And from the perspective of what is done in the laboratory, I believe we have a lot to offer in terms of bench-to-bedside research that could solve some of the major cardiovascular problems.”

An accomplished physician-scientist with expertise in translating basic science discoveries into practical applications to benefit patients, Dr. Wickline will complement USF Health’s growing cardiology service, and brings to USF a longstanding National Institutes of Health grant portfolio of more than $1 million a year.  He studies the molecular basis of inflammation, cell death and atherosclerosis that cause heart, vascular and other organ diseases.

Much of Dr. Wickline’s pioneering research explores the molecular basis of disease-causing processes using novel imaging methods to detect the genetic signature of cells and deploying nanoparticles to treat a variety of cardiovascular conditions, including targeting atherosclerotic plaques that cause heart attacks. His academic entrepreneurial work has led to the development of advanced cardiac imaging techniques, such as magnetic resonance imaging of the heart to assess coronary artery disease.

Dr. Wickline earned his MD degree from the University of Hawaii School of Medicine, and completed his residency in internal medicine and fellowship in cardiology at Washington University School of Medicine, in St Louis.

During his career at Washington University, Dr. Wickline served as chief of cardiology at Jewish Hospital and helped establish the university’s first graduate program in biomedical engineering. He led a consortium that works with academic and industry partners to develop broad-based clinical applications for nanotechnology and imaging.  He also established the Siteman Center of Cancer Nanotechnology Excellence with National Institutes of Health funding.

Dr. Wickline has started four biotechnology companies, holds numerous patents, and has authored more than 300 peer-reviewed research papers.

-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. USF Health is an integral part of the University of South Florida, a high-impact, global research university dedicated to student success. For more information, visit www.health.usf.edu

Media contact:
Anne DeLotto Baier, USF Health Communications
abaier@health.usf.edu or (813) 974-3303

Samuel A. Wickline, MD, has been named the first director of the USF Health Heart Institute – an important step in realizing USF Health’s goal of creating a world class cardiovascular medicine and research program at the University of South Florida Morsani College of Medicine and Tampa General Hospital.

Dr. Wickline will join the University of South Florida on Dec. 1 from Washington University in St. Louis. There he is the J. Russell Hornsby Professor in Biomedical Sciences and a professor of medicine (cardiologist), with additional appointments in biomedical engineering, physics, and cell biology and physiology.

“Please join me in warmly welcoming Dr. Wickline to USF Health. I’d also like to thank Dr. Stephen Liggett and Dr. Arthur Labovitz for ably serving as co-directors of the Heart Institute during its early planning and design phase,” said Charles Lockwood, MD, senior vice president of USF Health and dean of the Morsani College of Medicine, in announcing Dr. Wickline’s appointment.

“With a foundation firmly in place, we look forward to Dr. Wickline’s leadership in helping us build a state-of the-art cardiovascular institute positioned to accelerate USF’s path to preeminence.”

Samuel Wickline, MD

At USF Health, Dr. Wickline will be instrumental in helping design, build, equip and staff our state-of-the-art Heart Institute to be co-located with the new Morsani College of Medicine in downtown Tampa. That will include recruiting a critical mass of cardiovascular scientists at the forefront of interdisciplinary biomedical research to define the root causes of heart and vascular disease leading to new diagnostics and treatments.

He will also serve as Associate Dean for Cardiovascular Research, the Tampa General Hospital Endowed Chair for Cardiovascular Research and a professor of cardiovascular sciences in the Morsani College of Medicine.

As an accomplished physician-scientist with expertise in bench-to-bedside research, Dr. Wickline will complement USF Health’s growing cardiology service, and will bring to the university a longstanding National Institutes of Health grant portfolio of more than $1 million a year.  He studies the molecular basis of inflammation, cell death and atherosclerosis that cause heart, vascular and other organ diseases.

Much of Dr. Wickline’s pioneering research explores the molecular basis of pathological processes using novel imaging methods to detect early cell signatures in vivo and then using nanoparticles to treat a variety of cardiovascular conditions, including targeting atherosclerotic plaques that cause heart attacks. His translational work has led to the development of advanced cardiac imaging techniques, such as magnetic resonance imaging of the heart to assess coronary artery disease.

Dr. Wickline earned his MD degree from the University of Hawaii School of Medicine, and completed his residency in internal medicine and fellowship in cardiology at Washington University School of Medicine, in St Louis, where he joined the faculty in 1987.

During his career at Washington University, Dr. Wickline served as chief of cardiology at Jewish Hospital and helped initiate the first graduate program in biomedical engineering at Washington University. He led a consortium that works with academic and industry partners to develop broad-based clinical applications for nanotechnology and imaging.  He also established the Siteman Center of Cancer Nanotechnology Excellence with NIH funding.

Dr. Wickline has started several biotechnology companies, holds 17 patents, and has authored more than 300 peer-reviewed research papers.

University of South Florida neonatologist Akhil Maheshwari, MD, and his team advance research to understand, detect and identify novel treatments for necrotizing enterocolitis, or NEC, a life-threatening inflammatory bowel disease that may afflict premature newborns.

“As we’ve become better at controlling lung disease in premature infants, NEC has emerged as the single largest killer of premature babies,” said Dr. Maheshwari, a physician-scientist who holds the Pamela and Leslie Muma Endowed Chair in Neonatology in the Department of Pediatrics,  USF Health Morsani College of Medicine. Dr. Maheshwari also serves as medical director of the Jennifer Leigh Muma Neonatal Intensive Care Unit (NICU) at Tampa General Hospital.

Akhil Maheshwari, MD, holds the Pamela and Leslie Muma Endowed Chair in Neonatology in the USF Health Department of Pediatrics.

   Listen to Dr. Maheshwari talk about the impact of NEC.

The serious gastrointestinal disorder happens when the small or large intestine becomes inflamed and the lining of the intestinal wall starts to die off.  In the United States, it affects up to 10 percent of extremely low birth weight infants (less than 3.5 lbs.), with a mortality rate of 50 percent. Among premature infants in developing countries, such as India or China, NEC is more common.

With advances in technology and best clinical care practices, more extremely preterm infants are surviving with fewer complications, but NEC remains one of the most challenging diseases confronting neonatologists and pediatric surgeons. The causes of the dreaded condition remain unclear, and there is no treatment.

Translational research enlightened by clinical experience

Caring for tiny, fragile patients in Tampa General Hospital’s NICU adds perspective to the research Dr. Maheshwari conducts in his laboratory at the Morsani College of Medicine. “The vantage point I have as a neonatologist lets me observe NEC in the clinical setting, and I strive in the laboratory to translate this information to understand its pathophysiology,” said the USF Health professor of pediatrics, molecular medicine, and public health.

Over the last decade, Dr. Maheshwari’s group, and others, have found that a third of all instances of NEC in extremely premature infants occurs within 48 hours of receiving a blood transfusion.  He was recently awarded a five-year, $1.5-million R01 grant from the National Heart, Blood and Lung Institute, National Institutes of Health, to understand how blood transfusions may cause bowel injury in premature infants and develop new ways to prevent or treat this condition.

The newborn patients treated at Tampa General Hospital’s Muma Neontal Intensive Care Unit by Dr. Maheshwari, the unit’s medical director, are the among the most fragile and sickest.

In the U.S., necrotizing enterocolitis, or NEC, affects up to 10 percent of extremely low birth weight infants (less than 3.5 lbs.), with a mortality rate of 50 percent.  Causes of the life-threatening inflammatory bowel disease, a focus of Dr. Maheshwari’s research, remain unclear.

   Dr. Maheshwari discusses his latest NIH grant.

Supported by the latest NIH grant, Dr. Maheshwari will use a newborn mouse model to test whether red blood cell transfusions induce intestinal injury, whether the underlying anemia present in almost all premature newborns aggravates this injury, or whether both play a role in causing NEC. The USF researchers will also evaluate whether several standard blood bank practices — longer red blood cell storage, red blood cell washing to remove potentially hazardous electrolytes, and irradiation of transfused blood to help reduce risk of infection — can alter the severity of intestinal injury.

While many critically ill premature infants are stabilized within their first two weeks in the neonatal intensive care unit, within the second to third week a small proportion experience rapid onset of NEC without warning. “I see infants in the unit who were doing well and then die suddenly,” Dr. Maheshwari said. “The impact of this disease can be devastating, both emotionally and in terms of health care costs.”

There is no definitive diagnostic test to identify the disease in its earliest stages; abdominal X-rays can only diagnose when NEC has progressed to severe intestinal damage, including sometimes bowel perforation or peritonitis, Dr. Maheshwari said. Consequently, clinicians err on the side of caution if they suspect NEC — monitoring the condition with X-rays and extensive bloodwork, halting regular feedings, administering IV fluids and antibiotics and counseling an anxious family about what to expect if a NEC diagnosis is confirmed.

“The number of infants in the NICU who undergo testing for NEC is about 10 times more than the number who actually have the disease,” he said.

Half of the babies with confirmed NEC require surgery to excise the damaged intestinal tissue, and 50 percent who go to the operating room die, Dr. Maheshwari said. “The other half who survive end up with anatomically short intestines, so they depend on IV nutrition and often develop nutritional and developmental deficiencies that can affect brain growth.  They are at risk for lifelong complications.”

Mohan Kumar Krishnan, PhD, a research associate in Dr. Maheshwari’s laboratory, uses quantitative real-time polymerase chain reaction (PCR) to monitor amplification of gene expression. The technique helps the researchers determine how the immune system is responding to bacteria in the gut.

Key findings of Dr. Maheshwari’s laboratory

Researchers now believe that three things must all be present in the premature infant’s gut for NEC to occur:  bacteria, inflammation, and a unique signature of white blood cells (monocytes and macrophages) not found in adults with inflammatory bowel diseases.

In addition to the study of red blood cell transfusion-associated NEC, Dr. Maheshwari’s team focuses on two other lines of investigation — determining whether modifying the premature infant’s feedings can alter the immature, hyper-inflammatory nature of macrophages and identifying how the bowel’s inflammatory response in a premature infant differs from that in an adult, so the macrophages might be modified to prevent or treat NEC. The researchers hypothesize that the aggravated inflammatory response seen in the bowels of preterm infants happens because these very small babies with immature immune systems have not yet formed the adaptive mechanisms needed to tolerate the bacteria in their guts.

Dr. Maheshwari (center) with his research team, from left to right: Mohan Kumar Krishnan, PhD, research associate; Tanjing Song, PhD; senior biological scientist; Chitra Palanivel, PhD, postdoctoral research scholar; Kopperuncholan Namachivayam, PhD, research associate; and Thais Queliz Pena, MD, neonatology fellow.

Among some of their most significant findings:

• First to show that premature infants may be at risk of NEC because of a lack of the protein known as transforming growth factor-β2 (TGF-β2), which suppresses inflammatory responses.

• Demonstrated that infants whose bowel injury escalates to NEC have low blood levels of TGFβ2 since birth. “TGFβ2 is the first biomarker that can be obtained on day 1 to help predict which infants are most likely to develop NEC. Its 60-percent accuracy rate is still a six-fold improvement over the way we predict NEC now – by degree of prematurity,” Dr. Maheshwari said.

• While mothers who deliver preterm infants produce breast milk containing a large amount of TGF-β2, Dr.Maheshwari found that the beneficial growth factor in the mothers’ milk is largely biologically inactive. The USF researchers are investigating ways to activate the mother’s milk-borne TGFβ2 – in essence stimulating the milk to undergo the maturation needed to suppress unnecessary inflammation and protect the baby against NEC.

• Discovered that an acute drop in monocyte count in premature infants could be used as a diagnostic test to differentiate NEC from more benign causes of feeding intolerance like prematurity itself. A study led by Dr. Maheshwari found that 70 percent of premature infants with NEC experienced more than a 20-percent drop in monocytes in their blood.

• Recently identified a unique subtype of monocyte, formed in the newborn’s liver, which infiltrates the intestine of premature infants and may promote bowel injury. The subtype could be a new target for treating NEC.

   Dr. Maheshwari gives an example of how a laboratory discovery may change clinical practice.

Dr. Maheshwari was recently awarded a five-year, $1.5-million R01 grant from the NIH’s National Heart, Blood and Lung Institute to study how blood transfusions may cause bowel injury in premature infants and develop new ways to prevent or treat this condition.

In addition to his NIH-supported NEC research, Dr. Maheshwari has a $143,000 American Heart Association grant to study ways to block systemic inflammation and multi-organ dysfunction in very ill babies put on a treatment known extracorpeal membrane oxygenation (ECMO), which uses a heart-lung bypass machine.

“Dr Maheshwari’s work is highly innovative and has relevance well beyond the field of neonatology,” said Patricia Emmanuel, professor and chair of pediatrics at the USF Health Morsani College of Medicine.  “He brings great curiosity and passion to his research and is a wonderful role model for fellows and residents.”

Endowment key to  research benefitting tiniest newborns

The endowment by Pam and Les Muma to advance USF-TGH research and care for the sickest newborns helps support the infrastructure of Dr. Maheshwari’s highly specialized laboratory, including a machine that can measure a drop of a blood so tiny it fits on the head of a pin.

“Endowments are so critical,” Dr. Maheshwari said. “The equipment needed for the type of research we do is very specific for premature newborns, and doesn’t exist in most universities.”

Dr. Maheshwiari came to USF in 2014 from the University of Illinois at Chicago (UIC), where he was an associate professor pediatrics and chief of the Division of Neonatology. Prior to his tenure at UIC, he was an assistant professor at the University of Alabama at Birmingham and received several young investigator awards, including the American Gastroenterological Association Research Scholar Award and the Procter and Gamble GI Scholar Award.

The Muma endowment supports highly specialized equipment in Dr. Maheshwari’s neonatal research laboratory, including a machine that can measure a drop of a blood so tiny it fits on the head of a pin.

Dr. Maheshwari is a member of the editorial board of Maternal Health, Neonatology and Perinatology and several other professional journals and served on several grant review panels. He holds six provisional patents for new anti-inflammatory agents.

He earned his medical degree from the Institute of Medical Sciences, Varanasi, India, completed a pediatrics residency at the University of Florida, and received fellowship training in neonatology at USF.

Dr. Maheshwari with research associate Kopperuncholan Namachivayam, who works at a hematology analyzer that counts and separates various blood cell types including immune cells the researchers are interested in studying.

Photos by Eric Younghans, USF Health Communications

Bridging laboratory and clinical sciences, the study aims to improve the health outcomes  of pregnancies complicated by poor fetal growth

Tampa, FL (Sept. 28, 2015) – The USF Health Morsani College of Medicine has received a $4-million National Institutes of Health grant that will employ new imaging technologies and test biomarkers in the blood to determine whether abnormalities in the smallest blood vessels of the placenta and negative environmental influences, particularly smoking, cause fetal growth restriction (FGR).

The ultimate goal of the four-year study is to design a reliable way to predict poor growth of the fetus earlier in pregnancy so that physicians can intervene sooner to help prevent stillbirth, Cesarean delivery, decreased oxygen levels and other adverse outcomes.

The USF research award (1U01HD087213-01) was announced today as one of 19 projects funded by the Human Placenta Project — an initiative launched by the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Development to better understand the role of the placenta in health and disease.

Anthony Odibo, MD (left) and Umit Kayisli, PhD, of the USF Health Department of Obstetrics and Gynecology, are co-principal investigators of a $4-million Human Placenta Project — one of 19 new projects awarded in the U.S. and Canada by the NIH.

“I am so proud of our team,” said Charles J. Lockwood, MD,  dean of the USF Health Morsani College of Medicine and senior vice president for USF Health. “This is an important NIH initiative which addresses the common source of most major adverse pregnancy events – abnormal placentation.”

“In the past, it has been challenging to identify which women may benefit (from early therapeutic intervention), because they are at high risk for fetal growth restriction,” said co-principal investigator Anthony Odibo, MD, professor in the USF Department of Obstetrics and Gynecology.  “But powerful new imaging technology gives us the opportunity to really visualize all the blood vessels in the placenta, study the underlying problem of growth restriction, and create a highly predictive model for identifying small babies at risk of FGR.”

The USF grant, bridging laboratory and clinical sciences, will be led by Dr. Odibo and co-principal investigator Umit Kayisli, PhD, associate professor of obstetrics and gynecology.  Dr. Odibo, specializing in maternal-fetal medicine, is an expert in fetal therapy and directs the USF Fetal Care Center at Tampa General Hospital.  Dr. Kayisli specializes in molecular and cellular biology in reproduction and its clinical implications.

They will work on the NIH project with USF Ob/Gyn co-investigators Charles J. Lockwood, MD, Frederick Schatz, PhD, and Ozlem Guzeloglu-Kayisli, PhD, and with Rajendra Kedar, MD, from the USF Department of Radiology.  USF colleagues at Necker Hospital in Paris and at Oakland University William Beaumont School of Medicine in Rochester, MI, will also collaborate.

Fetal growth restriction (FGR), affecting up to 10 percent of all pregnancies, is commonly defined as fetal weight below the 10^th percentile for gestational age as determined by ultrasound. The condition remains a leading contributor worldwide to the death and illness of babies before and after birth.

Placental function – the ability of the critical organ to shuttle blood, oxygen and nutrients from mother to fetus through an intricate network of blood vessels – is inadequate in pregnancies complicated by FGR.  But predicting FGR has been difficult, because until recently imaging technologies have not been sensitive nor specific enough to clearly detect the smallest blood vessels in the placenta and monitor the flow of blood through this branching microvasculature.

Dr. Odibo points to an ultrasound image of the placenta, a critical organ that shuttles blood, oxygen and nutrients from mother to fetus through an intricate network of blood vessels.

For the USF study, researchers will use two of the latest technologies – superb microvascular imaging, or SMI ultrasound, and blood oxygen level-dependent magnetic resonance imaging, or BOLD MRI.

The investigators will compare biopsies of placenta from normal and FGR-complicated pregnancies in the laboratory and correlate them with the imaging assessments of the placental microvasculature.  They will also study how smoking affects the microvasculature and the potential link with FGR.

“The results obtained from SMI ultrasound and BOLD MRI combined with changes in expression levels of several biomarkers and epigenetic modifications in response to smoking will be instrumental in developing a predictive model for pregnancies at high risk for fetal growth restriction and improving the sensitivity and specificity of a potential early diagnosis and treatment of FGR,” Dr. Kayisli said.

For a list of all new grants awarded as part of the NIH Human Placenta Project, go to http://www.nichd.nih.gov/news/releases/Pages/092815-NIH-awards-HPP.aspx.

-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, and the USF Physician’s 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

Media contact:
Anne DeLotto Baier, USF Health Communications
(813) 974-3303 or abaier@health.usf.edu

Photos by Eric Younghans, USF Health Communications and Marketing

//www.youtube.com/watch?v=8Bf9W1POK_4

Distinguished USF Health Professor Cesario Borlongan, PhD, is internationally recognized for translational research on the neuroprotective and neurorestorative effects of stem cell therapies in stroke.

Over the last 22 years, his innovative work in the field of neuroscience has encompassed other neurodegenerative diseases and traumatic brain injury as well as stroke.  Dr. Borlongan, director of the Center of Excellence for Aging and Brain Repair at USF, does not hesitate to take calculated risks when it comes to following a different path of inquiry that may lead to a new discovery.

Take, for example, his recent study — with lead author Sandra Acosta, PhD, a postdoctoral fellow in Dr. Borlongan’s laboratory – published in the September issue of the American Heart Association journal Stroke.  The study showed that human bone marrow stem cells intravenously administered to post-stroke rats migrated to the spleen, an abdominal organ that plays a critical role in immune function, and significantly reduced chronic inflammation in the stroke brain.

“Next we want to explore whether transplanting these cells directly into the spleen, rather than peripherally, can lead to better functional recovery, including central nervous system improvement,” Dr. Borlongan said. “Even though stroke is a brain disorder, it has a major peripheral component – and in this case it may be the spleen that should be monitored more closely in our stroke patients.”

USF neuroscientist Cesario Borlongan, PhD, does not hesitate to take calculated risks when it comes to following a different path of inquiry that may lead to a new discovery.

In another study published in the journal PLOS ONE in 2013, Dr. Borlongan and colleagues suggested a new view of how stem cells may help repair the brain following trauma.   In a series of preclinical experiments they reported that transplanted cells appear to build a “biobridge” that links an uninjured brain site where new neural cells are born with the damaged region of the brain.  Based in part on the data reported by Dr. Borlongan’s group, the U.S. Food and Drug Administration approved a limited clinical trial to transplant SanBio 623 cells (an adult stem cell therapy) in patients with traumatic brain injury.  The trial has begun enrolling patients at Stanford University Medical Center.

Additionally, Dr. Borlongan’s bench to bedside research has led to to five FDA-approved clinical trials of cell transplantation in stroke, including the first cell therapy in adult stroke patients.

“One thing that distinguishes our center at USF from many others is its emphasis on translational research” he said. “We like basic science, but we want to see the discoveries in the petri dish translated to animal models of brain disorders and eventually go into the clinics…  At the end of the day, we ask the question:  Can this science be translated into saving lives and make a difference in the lives of patients with stroke and traumatic brain injury?”

National Institutes of Health (NIH) Scientist Emeritus Barry Hoffer, MD, PhD, says despite Dr. Borlongan’s relative youth as a scientist, his insight and creativity has yielded many discoveries advancing the understanding of ischemic brain injury, blood-brain barrier pathophysiology, traumatic brain injury, and stem cell transplantation.

“If I were to make a list of young neuroscientists who are already superstars, Dr. Borlongan would be at the top of my list,” said Dr. Hoffer, an adjunct professor of neurosurgery and proteomics and genomics at Case Western Reserve University School of Medicine.

Dr. Borlogan with Sandra Acosta, PhD, one of the postdoctoral fellows in his laboratory at the USF Center of Excellence for Aging and Brain Repair. “They are the ones who come up with the paradigm-shifting approaches to the experiments and drive the science,” he says of the trainees and students.

Dr. Borlongan has received continuous federal funding totaling more than $15 million from the U.S. Department of Veterans Affairs, the Department of Defense and the NIH since 2002 and also serves as the principal investigator on several industry grants.  Recently, he was awarded a two-year R21 grant from the National Institute of Neurological Disorders and Stroke to study the effects of endothelial stem cells on inflammation in the stroke vasculome — specific genes expressed on the interior surface of blood vessels in the brain following stroke.  The research may have implications for regulating inflammatory genes to treat chronic stroke.

The 30-member laboratory led by Dr. Borlongan includes graduate and doctoral students, a neurosurgery resident, and postdoctoral fellows – emerging scientists who contribute greatly to the research team’s vibrancy, innovation and passion for scientific discoveries.

“We need these young minds to challenge the existing paradigm. They are the ones who come up with the paradigm-shifting approaches to experiments and drive the science,” Dr. Borlongan said.  “I encourage, help facilitate and direct them to the literature, but it’s their show… I try to stay in the background rather than get in their way. That’s the most valuable thing I learned from my mentors.”

He also lets students know that it’s OK when experiments yield unexpected or negative results, because they can learn and move forward even if the initial hypothesis does not hold up. “Be logical, but follow the data; don’t change its direction,” he said. “It may lead you to something novel.”

Dr. Borlonghan with some of the emerging young scientists in his laboratory. They were recently filmed by LabTV.

Dr. Borlongan received his PhD in physiological psychology in 1994 at Keio University in Tokyo, Japan. He pursued fellowships in neuroscience at USF and the NIH, National Institute on Drug Abuse.  He was an associate professor at Medical College of Georgia, where he directed the Department of Neurology Cell Transplantation, before returning to USF as a faculty member in 2008.

He regularly serves on peer review panels for the NIH, VA and the American Heart Association and is an editorial board member for numerous scientific journals, including Cerebral Blood Flow and Metabolism, Stem Cells, PLOS ONE and Brain Research.  He holds several patents for inventions related to investigational cell therapies for brain disorders.

A fellow of the American Association for the Advancement of Science and member of the USF chapter of the National Academy of Inventors, Dr. Borlongan is 2015-16 president of the American Society for Neural Therapy and Repair.

Photos and video by Sandra Roa,  USF Health Communications and Marketing