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.”

Physician-scientist Dr. Sarah Yuan will expand her nationally prominent microvascular research program to include COVID-19

TAMPA, Fla. — Sarah Yuan, MD, PhD, professor and chair of the Department of Molecular Pharmacology and Physiology at the USF Health Morsani College of Medicine, has received a highly competitive National Heart, Lung, and Blood Institute (NHLBI) Outstanding Investigator Award to continue breaking new ground in microvascular and circulation research.

Dr. Yuan is the first USF faculty member to receive this particular award — $6.25 million from the National Institute of Health’s NHLBI to support her ambitious research program, instead of funding individual projects, over the next seven years.

Sarah Yuan, MD, PhD

The NHLBI Outstanding Investigator Award (OIA) recognizes scientists who have a track record of highly successful and innovative research and are considered likely to make major advances in heart, lung, blood or sleep research with the support of long-term, stable funding. Recipients of the prestigious award also demonstrate outstanding mentorship of students and junior scientists and leadership in cardiovascular research.

“I am so excited to receive this award because it provides long-term support for my work at a high level and allows tremendous freedom and flexibility to pursue research directions in newly emerging areas,” said Dr. Yuan, who trained as a trauma surgeon early in her career and has a secondary appointment as a professor of surgery. She also holds the Deriso Endowed Chair in Cardiovascular Disease at USF Health.

“I feel honored to have been recognized at the national level, and want to thank Dr. Charles Lockwood (USF Health senior vice president and Morsani College of Medicine dean) for supporting this application as well as the development of my research program,” she added. “I hope this will help expand our grant portfolio for cardiovascular and lung research at USF Health.”

Dr. Yuan’s research encompasses investigation of the loss of small blood vessel integrity during inflammation with the aim of discovering new diagnostics and treatments targeting vascular inflammation. With the Outstanding Investigator Award, she plans to broaden her research to look for tissue-specific biomarkers that might be used to diagnose and treat COVID-19, a respiratory virus that attacks the endothelial cells lining blood vessels and causes inflammation and damage in the lungs, heart, kidneys, brain and gut.

“Blood vessels supply every organ and tissue in the body,” she said. “So I’m fortunate that my research can apply to many types of disease processes, including investigating the COVID-19 host immune response characterized by blood vessel abnormalities, clotting, and circulation problems in multiple organ systems.”

A nationally recognized leader who studies the interactions between blood cells and endothelial cells, Dr. Yuan has developed cutting-edge theories on the molecular processes controlling microvascular permeability under normal and disease conditions. Through microvascular permeability (or leakiness) – an early step in the body’s inflammatory response to injury or to invading viruses, bacteria or other pathogens – the blood vessel wall allows the flow of fluid, proteins, small molecules, or white blood cells (neutrophils) on their way to the site of inflammation.

Dr. Yuan’s discoveries have significantly advanced the understanding of the complex interplay between signaling molecules and endothelial structures that regulate vascular barrier function during trauma, infection, sepsis, ischemia/reperfusion injury, atherosclerosis, and diabetes. She identified several molecules that play key roles in mediating leakage from blood vessel walls. Her laboratory has pioneered molecular biology and imaging techniques to learn more about how the vascular barrier malfunctions, which can lead to excessive leaking of fluid and proteins from blood vessels, tissue swelling and ultimately organ failure.

Dr. Yuan’s laboratory has pioneered molecular biology and imaging techniques to learn more about the permeability of tiny blood vessels and how the vascular barrier malfunctions. She uses the state-of-the-art resources at USF Health’s Muma Advanced Microscopy and Cell Imaging Core facility.

Throughout her career Dr. Yuan has emphasized the translational value of research work that links novel molecular findings to the physiological processes underlying injury and illness through rigorous analysis of human models of disease, as well as animal models and cell cultures. Using trauma patient blood samples, Dr. Yuan is collaborating with David J. Smith, MD, professor and chair of the USF Health Department of Plastic Surgery, to identify novel diagnostic markers of inflammatory injury that might better guide the precision treatment of trauma and burns, as well as prevent secondary infection and other complications.

Dr. Yuan has been continuously funded by the NHLBI for more than 25 years. She is the author of more than 85 peer-reviewed articles in high-impact journals, including Nature Communications, Circulation, Circulation Research, Cardiovascular Research, and Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB). She is a fellow of the American Association for the Advancement of Science and the 2020 recipient of the Eugene M. Landis Award from The Microcirculatory Society.

Dr. Yuan has served on numerous NIH study sections and work groups. She is currently a regular member of a standing NIH study section, Hypertension and Microcirculation, and she routinely participates in NIH grant reviews for other areas, including the Surgery, Anesthesiology and Trauma, the Vascular Biology and Hematology, and the Surgical Sciences, Biomedical Imaging and Bioengineering panels.

-Photos by Allison Long, USF Health Communications and Marketing

Sarah Yuan, MD, PhD, professor and chair of the USF Health Morsani College of Medicine’s Department of Molecular Pharmacology and Physiology, has received the 2020 Eugene M. Landis Award for her outstanding contributions to the field of microvascular research.

The top award is bestowed by The Microcirculatory Society to a member and active investigator who conducts and publishes meritorious research advancing the understanding of microcirculation.  Microcirculation comprises all small blood vessels in tissue and organs and their contents (blood plasma and blood cells).

Sarah Yuan, MD, PhD

Dr. Yuan also has an appointment as a professor in the Department of Surgery and holds the Deriso Endowed Chair in Cardiovascular Disease at USF Health.  A nationally recognized leader in investigating the interactions of blood cells and endothelial cells that line the inner surface of blood vessels, she has developed cutting-edge theories on the molecular mechanisms controlling microvascular permeability during both normal and disease-causing conditions. Her discoveries have significantly advanced the understanding of complex interactions between signaling molecules and endothelial structural elements that regulate vascular barrier function during inflammation, trauma, infection, sepsis, atherosclerosis, and diabetes. She has created innovative techniques, including the cannulated venule model for measuring permeability and protein/DNA transfection to intact isolated microvessels.

Continuously funded by the National Institutes of Health throughout her career, Dr. Yuan has been awarded more than $16.5 million in NIH funding for microcirculation research as a principal investigator over the last 10 years. She publishes papers typically appearing in high-impact journals such as Nature Communications, Circulation, Circulation Research, Cardiovascular Research, and Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).

Last month, Dr. Yuan was among nine USF researchers, and 450 from across the country, named a new fellow of the American Association for the Advancement of Science (AAAS).

Through her influential publications, extensive service on NIH grant review panels, successful mentoring of junior scientists, and creation of opportunities for others, Dr. Yuan continues to guide the national research agenda focused on microcirculation.

-Photo by Allison Long, USF Health Communications and Marketing

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’s pathobiology expert Sarah Y. Yuan, PhD, is among nine USF researchers, and 450 from across the country, named new fellows of the American Association for the Advancement of Science (AAAS). The honor, announced Nov. 26, is one of the most prestigious among academic researchers worldwide.

AAAS is the world’s largest scientific society, recognizing research and scholarly excellence in fields ranging from engineering to health sciences. Election as an AAAS fellow is an honor bestowed upon AAAS members by their peers.

Dr. Yuan, professor and chair of the Department of Molecular Pharmacology and Physiology in the USF Health Morsani College of Medicine, was named a fellow in the Medical Sciences Section of AAAS. Dr. Yuan holds the Deriso Endowed Chair in Cardiovascular Disease at USF Health and is a national leader in translational cardiovascular research. Her AAAS citation noted: For distinguished contributions in advancing molecular pathophysiology of trauma, sepsis, atherosclerosis, diabetes; particularly for developing paradigm-shifting theories and imaging technologies in microvascular permeability.

As an AAAS Fellow, Dr. Yuan is among some of USF’s most accomplished faculty members, representing decades of scientific accomplishments.

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Jerome Breslin studies what happens when the endothelial barrier is breeched by traumatic injury and inflammation

Traumatic injury is the leading cause of death among people ages 1 to 44 in the United States. The body’s inflammatory response accompanying massive injury can severely complicate the resuscitation of trauma victims, worsen clinical outcomes and often lead to multiple organ failure.

In his laboratory at the USF Health Morsani College of Medicine, Jerome Breslin, PhD, and colleagues study microvascular hyperpermeability, that is, the “excessively leaky” small blood vessels that are a hallmark of systemic inflammation.  Their aim is to find new, more effective ways to treat trauma and prevent early death, but their work also has implications for the treatment of lymphedema, wound healing and arteriosclerosis.

Jerome Breslin, PhD, can do live imaging of vascular endothelial cells under a microscope that he helped build.

In particular, Dr. Breslin, an associate professor in the Department of Molecular Pharmacology and Physiology, looks at what happens when the protective barrier of endothelial cells forming an interface between circulating blood and tissues outside the blood vessel network is compromised by traumatic injury and inflammation.

Leaky blood vessels: The soaker hose analogy

“These capillaries are like soaker hoses used to water plants, that leak out fluid carrying proteins and other nutrients in addition to delivering oxygen to surrounding tissue,” Dr. Breslin said. “In patients who have undergone trauma or major surgery, blood pressure drops in part because the wall of the hose becomes too leaky. There is less fluid in the blood vessels and more flowing out into nearby tissues, which can cause damage and impair the function of some organs.”

In addition to investigating ways to prevent excessive blood vessel leakage, Dr. Breslin’s lab focuses on how to return the leaked fluid back into the blood by the lymphatic vessels.  As a result, his team spends a lot of time studying the pumping function of the lymphatic system, which manages fluid levels in the body. Swelling, or edema, occurs when it fails to drain off excess fluid.

Dr. Breslin’s work is currently supported by two National Institutes of Health RO1 grants totaling more than $2 million.

Dr. Breslin with two undergraduate students who conduct research in his laboratory: Andrea Burgess (American Physiological Society IOSP Summer Fellow) and Sara Spampinato, center (NIH Diversity Grant recipient).

 Dr. Breslin comments on his approach to research problems.

The most recent award from the NIH’s National Institute of General Medical Sciences focuses on testing whether a class of drugs that activate the S1P1 receptor may keep blood vessels from leaking too much and stabilize blood pressure following trauma.

In this project, Dr. Breslin will use the first rat model combining alcohol intoxication and hemorrhagic shock to induce excessive leakiness in small blood vessels. He will evaluate whether fluid containing sphingosine-1-phosphate (S1P) reduces the blood vessel permeability, thereby restoring normal blood pressure and fluid balance. If so, Dr. Breslin said, drugs similar to S1P, a bioactive lipid that prevents cell death, may offer a more effective way for paramedics and physicians to resuscitate trauma patients than the standard IV fluid therapy now administered.  That standard fluid resuscitation protocol works particularly poorly in alcohol-intoxicated victims suffering major blood loss, a significant portion of all trauma cases coming through emergency rooms, he said.

With the second award, a competitive renewal from the NIH’s National Heart, Blood and Lung Institute, Dr. Breslin and colleagues are studying the molecular and cellular mechanisms that may regulate and resolve microvascular leakage following inflammation caused by traumatic injury.

Dr. Breslin points to a human heart valve suspended in a test tube solution. His group plans to study the microvessels within heart valves.

Unexpected finding leads to “new way of thinking”

Previous work by his group using live imaging of vascular endothelial cells under a microscope demonstrated that when the edges of these cells make contact with their neighboring cells they appear very active and are constantly remodeling, or changing shape — rapidly opening up holes at cell junctions and then closing back up. This finding, published in the journal PLOS One, countered one of the conventional theories that endothelial cells were more rigid at the junctions where they connect and adopted a contracted state during inflammation.

“It was an unexpected finding that changed our thinking about how these cells behaved,” Dr. Breslin said.

This led the researchers to begin to question the prevailing view about the role actin stress fibers — threadlike structures involved in cell stability, adhesion and movement — play in disrupting the endothelial barrier function.

Further preclinical studies by Dr. Breslin and others over several years showed that in response to an inflammatory agent actin stress fibers cause endothelial cells to spread out, not contract, at the junctions. The USF researchers published evidence in the American Journal of Physiology: Cell Physiology that actin stress fiber formation may be a reaction to, rather than a cause of, reduced integrity of the endothelial barrier that protects against excessive fluid leakage.

Earlier this year, Dr. Breslin was first author on a study appearing in the Journal of the American Heart Association showing that the signaling protein Rnd3 reduced leakage of small blood vessels when delivered a new way in a rat model of hemorrhagic shock. The researchers suggested Rnd3 (or analog drugs) might offer an anti-inflammatory treatment to repair the endothelial barrier compromised by prolonged and uncontrolled inflammation.

  Dr. Breslin talks about his most exciting experiment

//www.youtube.com/watch?v=lm2ag8m1QqQ

Live imaging of endothelial microvascular cells at 600x magnification shows the dynamic movement of the protruding cell edges (local lamellipodia). Videoclip courtesy of Jerome Breslin, PhD. 

Heart Institute, former mentor a draw to USF

Dr. Breslin joined USF in 2012 from Louisiana State University Health Sciences Center in New Orleans, where he was an assistant professor of physiology.  He received his PhD in pharmacology and physiology from Rutgers University – New Jersey Medical School in Newark, NJ.  His postdoctoral training was conducted at both Texas A&M and the School of Medicine at the University of California Davis, where he was mentored by Sarah Yuan, MD, PhD, the chair of Molecular Pharmacology at Physiology at Morsani College of Medicine who is nationally recognized for her translational research on the regulation of microcirculation.

The opportunity to be part of a growing university, join core faculty who will help build a Heart Institute advancing bench-to-bedside cardiovascular research, and work again with Dr. Yuan attracted him to USF Health, Dr. Breslin said.

“Dr. Yuan was a great mentor to me when I was a postdoctoral fellow,” he said. “This has reopened our scientific collaborations and now we’re mentoring a student together.”

Dr. Breslin, center, with some members of his laboratory.

  His advice to emerging scientists

Dr. Breslin is a fellow of the American Physiological Society Cardiovascular Section and a member of The Microcirculatory Society and the American Heart Association.  He is associate editor of the journal Microcirculation and a member of the editorial board of PLOS One.  He has authored or co-authored nearly 40 articles in peer-reviewed journals.

Dr. Breslin serves on two NIH special emphasis panels, one on lymphatics and another for the Intramural Postdoctoral Research Associate Program.  He is also a grant reviewer for the Association of American Medical Colleges (AAMC) Innovations in Research and Research Education Awards.

Something you may not know about Dr. Breslin

To help pay for tuition while earning his master’s degree in biology, Dr. Breslin worked as a park ranger in Somerset County, N.J, for a couple of summers.

No stranger to outdoor activities, including camping, as a teen Dr. Breslin attained the rank of Eagle Scout, the highest achievement in the Boy Scouting program.  His connection with scouting continues today as committee chair for his 13-year-old son’s Boy Scout troop.

Dr. Breslin’s Scouting experiences included learning wilderness survival skills, such as how to build a shelter from scratch in the woods or navigating a group of boys through the wilderness without a map and compass, or a smartphone for that matter. They were instrumental, he said, in helping him develop the resourcefulness and leadership skills he hopes to impart to the emerging scientists he mentors in his laboratory

In case you’re wondering, one of the most challenging of the merit badges he earned as a Boy Scout: bugling.

Photos and audioclips by Sandra C. Roa, USF Health Communications and Marketing