The program, one of five awarded nationally this year, pairs faculty mentors from USF Health’s Heart Institute with promising students interested in cardiovascular or related biomedical research

The American Heart Association has awarded the USF Health Morsani College of Medicine a three-year, $60,000 grant to establish a summer training program intended to encourage promising undergraduate college students from all disciplines to consider careers in cardiovascular research.

The AHA-sponsored Undergraduate Student Fellowship grant was one of five newly awarded in 2018 to institutions across the United States. And, the 13 total undergraduate student fellowship programs currently funded by AHA include such prestigious institutions as Stanford University, the University of California San Diego, Pennsylvania State University and Carnegie Mellon University, to name a few.

USF Health’s Heart Institute Summer Undergraduate Research Fellowships program begins May 28, providing a 10-week research experience for five highly qualified junior and senior-level undergraduate students. This summer, all five student fellows entering the rigorous program are from USF, but qualifying U.S. and international students from other institutions can apply.  The AHA grant funds $4,000 stipends to support each trainee.

Jerome Breslin, PhD, professor in the USF Health Department of Molecular Pharmacology and Physiology, directs the newly awarded Summer Undergraduate Research Fellowships program sponsored by the American Heart Association. Dr. Breslin is pictured here in 2016 with two USF undergraduate students who conducted NIH and American Physiological Society fellowship-supported research in his laboratory — Sara Sampinato (left), chemical engineering major, and Andrea Burgess, biomedical sciences major. |Photo by Eric Younghans

“Our main goal is to recruit, train and mentor outstanding undergraduate students so they can become the next generation of graduate students and medical students who will be future leaders and advocates for cardiovascular research,” said Jerome Breslin, PhD, professor in the Department of Molecular Pharmacology and Physiology who directs this new AHA fellowship program at USF.

Five faculty members — all members of the USF Health Heart Institute with a solid track record of producing successful scientists — will mentor the undergraduate fellows through their individualized summer research experiences. Four faculty mentors are from Molecular Pharmacology and Physiology: Dr Breslin; Ruisheng Liu, MD, PhD, professor; Sami Noujaim, PhD, assistant professor; and Sarah Yuan, MD, PhD, departmental chair and professor. The fifth, Mack Wu, MD, holds appointments as a professor in the Department of Surgery and the Department of Molecular Medicine.

Graduate and doctoral students will also help mentor, giving the undergraduates an opportunity to interact with researchers at all levels, Dr. Breslin said.

The students will train in laboratories using cutting-edge technology to better understand the underlying mechanisms of diseases and discover new therapies.  Their cardiovascular research projects will focus on basic science areas in which the Heart Institute investigators are experts, including:  endothelial function, microcirculation, hypertension and cardiac arrhythmias.

In addition to laboratory research, students will participate in weekly seminars and workshops designed to instill scientific rigor, develop professional skills, and help them begin building a network needed to pursue a career in science.

“At the USF Health Heart Institute, we want to create the most vibrant research environment possible for all levels of trainees. That means reaching out to students who are still undergraduates to nurture their interest in cardiovascular or related biomedical sciences with a meaningful summer research experience. Ultimately we want to get more young scientists into the pipeline – and it’s never too early to start that process.”

This summer, the five student fellows participating in the AHA program were selected from among 18 applicants, including several from the University of Florida and Florida State University.  For the first summer, all these undergraduate participants are from USF:

USF Juniors (all majoring in biomedical sciences)
Nouhaila Beytour, Dr. Noujaim (faculty mentor); Veneta Dinova, Dr. Liu; Rebeca Gonzalez Jauregui, Dr. Breslin; and Ethan Zheng, Dr. Yuan.

USF Senior (majoring in public health)
Forouzandeh Farsaei, Dr. Breslin

For more information, please visit: www.health.usf.edu/medicine/mpp/surp.

Understanding the sensory nerves involved in protective behaviors may lead to new therapies for respiratory, cardiovascular diseases

Think about the last time you stubbed a toe.

The sensory nerves activated when your toe slammed against a hard object initiated a defensive reflex leading you to withdraw your toe from the source of intense pain. Tom Taylor-Clark, PhD, associate professor in the Department of Molecular Pharmacology and Physiology, likens the pain-induced response to an early warning system that, if working properly, helps us avoid things that can cause damage.

“If you stub your toe once, sure it hurts so much,” he said, “but if you do it repeatedly, eventually you will break your toe.”

In his laboratory at the USF Health Morsani College of Medicine, Dr. Taylor-Clark studies the role of defensive, or nociceptive, sensory nerves in health and disease. Using a combination of electrophysiology, imaging and molecular biology techniques, he investigates how these peripheral nerves, which stimulate organs and penetrate nearly all the body’s tissues, sense their environment. That includes sensory nerve response to external stimuli, like extreme heat or cold, inhaled pollutants or a source of injury, and internal stimuli, such as inflammation, infection or organ damage.

Thomas Taylor-Clark, PhD, an associate professor in the Department of Molecular Pharmacology and Physiology, studies the role of defensive, sensory nerves in health and disease.

“We are interested in understanding the sensory nerves involved in protective behaviors, or defense, because they are the ones that go wrong in disease and injury,” Dr. Taylor-Clark said.

The protective role of airway sensory nerves in cough

His laboratory focuses primarily on the electrical excitability of sensory nerves of the airways. The researchers study the behavior of sensory nerves connecting the lungs with the brainstem, the primitive part of the brain that controls basic body functions such as breathing, swallowing and heart rate. In particular, Dr. Taylor-Clark works with colleagues to better understand the nerves involved in initiating the chronic cough associated with the asthma, a disease characterized by persistent airway inflammation.

Knowing more about how these airway sensory nerves work, including the interface between the conscious and unconscious in the brainstem networks that control cough, is important in understanding how they are disrupted by inflammatory disease. The information could help guide the design of new treatments for unresolved cough and associated symptoms, a major reason people visit primary care providers, Dr. Taylor-Clark said. In addition, better ways to treat cough are important, because for those with a variety of neuromuscular diseases impaired cough can cause an increase in pulmonary infections from aspiration.

Recently, Dr. Taylor-Clark’s team expanded their research to look into how pre-existing cardiovascular disease alters nerve-generated reflexes from the lungs to affect cardiovascular function.

 Dr. Taylor-Clark comments on one aspect of his laboratory’s sensory nerve research.

Stephen Hadley, a senior biological scientist in Dr. Taylor-Clark’s laboratory.

Three research awards totaling more than $2.85 million support their work. The studies are done using cell cultures as well as with the help of transgenic mice that selectively express red fluorescent protein in defensive neurons.

With a grant from the National Heart, Blood and Lung Institute, Dr. Taylor-Clark has investigated the connection between two well-known research findings to determine the downstream effects of mitochondria, the energy producers of the cell, on airway sensory nerve activation. The first finding, he said, was that airway sensory nerves respond to a type of inflammatory signaling that induces potentially damaging oxidative stress. The second was that mitochondria are located right next to signaling receptors in the sensory nerve cells.

“So, we hypothesized that perhaps mitochondria are not there just to produce energy, but to generate signaling,” Dr. Taylor-Clark said. “And we found that mitochondrial signaling activates the sensory nerves specifically by activating chili and wasabi receptors in airways.”

Hot on the trail of wasabi and chili receptors

These receptors for chili peppers (or capsaicin) and wasabi (allylisothiocyanate), officially known as TRPV1 and TRPA1 respectively, are expressed by every single defensive sensory nerve in your body, including those in your tongue, your skin – and your airways (nasal passages, bronchi, larynx). Together the TRPV1 and TRPA1 compounds contribute to involuntary cough reflex.

The USF work linking mitochondrial signaling and airway sensory nerve receptors, triggered by these TRPV1 and TRPA1 molecules that can generate pain as well as heat sensation, resulted in two major papers in the journal Molecular Pharmacology, one in 2013 and another in 2014. A supplementary biophysiological study defining how the wasabi (TRPA1) receptor works was published earlier this year in the Journal of General Physiology.

Above and below: Microscopic images from a transgenic mouse expressing the red fluorescent protein tdTomato  in defensive sensory nerve only.  This crosssection of the lung showing defensive nerve terminals (red)  innervating regions surrounding the small branches of bronchiles, or air tubes (green), within the lungs.

A slice of the brainstem showing central projections of defensive nerves (red) into the medulla, where the nerves transmit signals to brainstem networks to control various involuntary functions like breathing, cough, swallowing, heart rate and blood pressure.

Pollution-induced exacerbation of underlying cardiovascular disease

Another direction of scientific endeavor for Dr. Taylor-Clark is investigating how pre-existing cardiovascular disease may alter normal reflexes from the lungs to affect autonomic regulatory control of the heart. Seed funding from an earlier Morsani College of Medicine Research Office intramural BOOST grant helped his research group obtain a two-year American Heart Association award for this more recent area of research under the auspices of the USF Health Heart Institute.

In preliminary research presented last year at the Experimental Biology Conference, Dr. Taylor-Clark and colleagues reported that hypertensive rats exposed to wasabi, an irritant mimicking the effects of a pollutant like ozone when inhaled into the lungs, experience a much different cardiac response than healthy rats. The heart rate of healthy rats exposed to wasabi slows significantly as a protective mechanism to help slow the distribution of pollutants throughout the body. But given the same exposure, rats with chronic high blood pressure have periods of rapid heartbeats interspersed with a slow heart rate – which can evoke a potentially dangerous abnormal heart rhythm known as premature ventricular contractions.

“So you have a situation where you’ve gone from a healthy (cardiovascular) reflex to an aberrant reflex that may exacerbate pre-existing cardiovascular disease,” he said.

Working with researchers at the University of Florida, Dr. Taylor-Clark is a co-investigator for a recently awarded a three-year, $1.28M grant from the National Institutes of Health Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) funding program. The comprehensive project aims to improve maps of the peripheral nervous system —the electrical wiring that connects the brain and spinal cord with the rest of the body – so that more selective and minimally invasive “electroceutical” treatments might be developed for conditions such as heart disease, asthma and gastrointestinal disorders.

 USF’s involvement in NIH project charting defensive airway nerves.

Dr. Taylor-Clark and Stephen Hadley. Recently, Dr. Taylor-Clark’s laboratory expanded its research to look into how pre-existing cardiovascular disease alters nerve-generated reflexes from the lungs to affect cardiovascular function.

Mapping for the future of neuromodulation therapies

The UF-USF multidisciplinary team is focusing on functional mapping of peripheral and central neural circuits for airway protection and breathing.

Using cutting-edge genetic and neurophysiological approaches, they are characterizing the types of defensive airway nerves that control breathing, coughing and heart rate differently and finding where they connect into the brainstem network.

“We are trying to bridge the gap between what has been done (with nerve trafficking) in the lungs and what has been done in the brainstem, and then link them together,” Dr. Taylor-Clark said. “We have transgenic mice that make red fluorescent protein only in their defensive nerves, so now we can chart where targeted nerves are going with superior image quality.”

The team’s overall goal is to advance understanding of the neural pathways underlying respiratory control, laying the groundwork for future neuromodulation therapies to normalize lung function in people at risk.

“If we want to (preferentially) target these therapies for optimal effectiveness, we need to know where all these nerves go and what they do,” Dr. Taylor-Clark said.

Dr. Taylor Clark-received his PhD degree from University College London in 2004. He completed a postdoctoral fellowship at Johns Hopkins University Division of Allergy and Clinical Immunology and served as a medical faculty member at Hopkins for a year before joining USF’s medical school in 2009 as an assistant professor.

Dr. Taylor-Clark is associate chair for research in the Department of Molecular Pharmacology and Physiology. In 2015, he received the Award for Excellence in Teaching from USF’s Graduate PhD Program in Integrated Biological Sciences.

 How mapping neural circuits for airway protection and breathing may lead to novel therapies.

A combination of electrophysiology, imaging and molecular biology techniques are used to study behavior of sensory nerves connecting the lungs with the brainstem.

Some things you might not know about Dr. Taylor-Clark:

• In the mid-1990s, for two years before entering University College London as an undergraduate, he played bass guitar in a band that recorded and performed “very loud rock and roll” as part of the London music scene. These days, with wife Luciana as the audience, Dr. Taylor-Clark jams at home in his living room with daughter Ella, 9, who plays drums.

• Taylor-Clark’s PhD thesis involved a study of how the human nose congests. He measured the internal dimensions of people’s nasal passages with a sonar device at the end of a stick, recruiting family and friends, among others, as study volunteers. He induced sneezing and other symptoms of hay fever by spraying histamine into their nostrils. The shape of the nose and the interaction between nerves and blood vessels in the nose affected air flow and severity of symptoms, he discovered. “While writing the thesis, I began to realize how little was understood about nerves in the airways.”

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 Photos by Eric Younghans, USF Health Communications

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

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

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

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

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

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

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

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

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

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

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

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

Details:

AHA Heart Walk – Tampa

Saturday, Nov. 7

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

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