Graduate programs at USF Health had promising gains in this year’s rankings from U.S. News & World Report (U.S. News), with some programs breaking into the top 50 of their rankings.

In the U.S. News 2024 Best Graduate Schools list released on April 25, USF Health’s physician assistant, nursing and public health programs ranked among the best in the country.

The rankings released April 25 did not include medical schools or law schools; those rankings were released by U.S. News May 11.

Among the notable advancements this year are the two graduate programs from the USF Health College of Nursing, each of which had major gains, and the Physician Assistant Program in the USF Health Morsani College of Medicine, which made the ranking list for the first time in its young history after receiving its inaugural full accreditation needed to qualify.

“Our nursing school is clearly garnering attention on the national stage as both its master’s and doctoral programs are making incredible gains in the rankings, and proving to be the best in Florida,” said Charles J. Lockwood, MD, MHCM, executive vice president of USF Health and dean of the USF Health Morsani College of Medicine. “And the first-time ranking for our physician assistant program marks a significant milestone. While this USF Health program is still young, its inaugural ranking is among the top third of PA programs across the country. We anticipate further rankings gains as our program continues to develop.”

According to U.S. News, its methodology uses data from expert opinions and statistical indicators when measuring a program’s ranking, examining qualities students and faculty bring to the educational experience and graduates’ achievements linked to their degrees, such as job placement and research impact.

The posted results for USF Health this year include:

• #46 in Medical Schools for Primary Care: The USF Health Morsani College of Medicine improved significantly for U.S. medical schools for primary care, going from #56 last year to #46 this year, and breaking into the top 50 for the first time.
• #50 in Medical Schools for Research: The Morsani College of Medicine continues to rank well among U.S. medical schools for research, ranking at #50 this year.
• #65 in Health Doctoral Programs – Physician Assistant: The Morsani College of Medicine’s Physician Assistant program ranked for the first time, ranked at #65 this year, placing it in the top third of the more than 200 PA programs in the rankings.
• #31 in Nursing for Master’s: The USF Health College of Nursing jumped 11 spots, going from #42 last year to #31 this year, making it the top-ranked public nursing master’s program in Florida.
• #33 in Nursing for DNP: The College of Nursing also continues to improve in its DNP program ranking and skyrocketed into the top 50 for doctoral programs in the country with its 34-spot jump from #67 last year to #33 this year, making it the top-ranked public or private DNP program in Florida.
• #22 in Public Health: The USF Health College of Public Health remains the top-ranked public health program in Florida, with its rank at #22 this year.

U.S. News does not provide new rankings for all graduate programs each year, so the USF Health Taneja College of Pharmacy maintains its rank of #68, and the School of Physical Therapy and Rehabilitation Sciences maintains its rank of #49.

More on rankings for other USF graduate programs…

This year’s USF Health Research Day set new records as more participants than ever filled the USF Tampa campus Marshall Student Center on March 3 to showcase the best of their scientific work.

The 33^rd USF Health Research Day included 457 research poster presentations by students, postdocs, residents, faculty, and staff across all health disciplines. Research Day is the largest research-oriented event of its kind at USF and remains the largest celebration of health sciences research collaboration across all four USF Health colleges (medicine, nursing, public health and pharmacy) as well as with colleagues in other USF colleges, including social work and engineering.

From left, Dr. Charles Lockwood, Dr. Kim Orth, Rhea Law, and Dr. Steve Liggett.

Research Day kicked off with the Annual Roy H. Behnke, MD, Distinguished Lectureship featuring speaker Kim Orth, PhD, professor of Molecular Biology and Biochemistry at University of Texas Southwestern Medical Center and an investigator at the Howard Hughes Medical Institute, at UT Southwestern Medical Center.

Dr. Orth’s presentation was titled “Black Spot, Black Death, Black Pearl: Tales of Bacterial Effectors” – click here for more about Dr. Orth and her work.

Dr. Kim Orth.

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Tampa General Hospital, the primary teaching hospital for USF Health Morsani College of Medicine, was the presenting sponsor for USF Health Research Day 2023.

Following Dr. Orth’s presentation was the judging of work. Judges reviewed the posters that lined the Marshall Center Ballroom, asking the students for more detail and clarifications about their research projects. Presentations ranged from pilot, preliminary, empirical and case studies to system reviews and reviews of literature or charts.

Following the 13^th Annual Joseph Krzanowski Invited Oral Presenters by select students representing medicine, nursing, public health, and pharmacy, Research Day culminated with an Awards Ceremony in the Oval Theatre announcing the winners in 29 competitive categories – including 18 monetary awards totaling $8,600.

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For the list of Research Day 2023 award winners, click here.

For the list of Research Day judges and sponsors, click here.

More photos

Photos by Freddie Coleman, video by Allison Long, USF Health Communications

The USF Health Morsani College of Medicine is the fastest-rising medical school in the country, climbing over the last decade from #80 to #46 in U.S. News & World Report rankings for medical schools for research.

Based on data from U.S. News & World Report Academic Insights, the Morsani College of Medicine has climbed 34 spots in rankings for 2014 to 2023. No other medical school in the data – public or private – has risen as far in rankings as fast as the Morsani College of Medicine.

In the last decade, the USF Health Morsani College of Medicine has made great strides, pushing metrics upward in the college’s three mission areas — education, research and patient care – in an effort to place the college among the best medical schools in the country.

With improved metrics, the college’s placement in the national rankings soared from No. 80 in the 2014 U.S. News list to No. 46 in the recently published 2023 list – a seismic 34 spots.

No other medical school in the country has experienced that same improvement in rankings, making the USF Health Morsani College of Medicine the fastest-rising medical schools in the country.

“Our sustained rise in national rankings reflects the rapidly increasing strength of our educational, research and clinical missions at the USF Health Morsani College of Medicine. We are now competing with the nation’s most storied and respected programs,” said Dr. Charles Lockwood, senior vice president for USF Health and dean of the USF Health Morsani College of Medicine. “These outstanding metrics also position us to attract the highest caliber students and faculty, further advancing our program into the national spotlight for its outstanding education, exceptional research and world class clinical care.”

Scientific research is often a low-key exercise, with fastidious people peering into microscopes and working under the radar. Seldom are they described as rising stars, but Jiajia Yang may have broken the mold.

This month, Dr. Yang became the first person to earn a PhD from USF through a new degree program within the newly opened USF Health Heart Institute.

The 30-year-old earned her degree in medical sciences from the USF Health Morsani College of Medicine, with a focus on heart disease, specifically genetic arrhythmia and cardiomyopathy gene mutations within a family.

The Heart Institute is housed within the new Morsani College of Medicine + Heart Institute building in the Water Street Tampa district of downtown Tampa. The facility, which also includes the MD degree program, opened in January 2020.

“You can’t imagine how excited I am,’’ Dr. Yang said of her degree and new career. “The most exciting part for me is that our research is really translational for patients. This isn’t just bedside to bench, but bench to bedside.’’

Originally from a small village in rural China, Dr. Yang attended medical school in Shanghai, then won a scholarship in 2015 at Descartes University in Paris. While there, she earned her Masters and learned to speak French ─ adding to her verbal portfolio of Chinese and English.

Dr. Thomas McDonald with Dr. Jiajia Yang.

After a year, she accepted a position as a research assistant at the USF Health Morsani College of Medicine and quickly showed promise as a fast and inquisitive learner, said Thomas McDonald, MD, professor in the Department of Molecular Pharmacology & Physiology. He would later work with Dr. Yang on a variety of heart-related research projects, including the role of patient-specific induced pluripotent stem cells.

“This is all technically difficult and she overcame so many obstacles,’’ Dr. McDonald said. “She really laid the ground work to help this take off.’’

During her time at USF, Dr. Yang published five research papers in peer-reviewed journals, including new findings on using patient-specific stem cells to study disease in human tissue.

“That had not been on the map at USF until now,’’ Dr. McDonald said. “Jiajia’s papers were the first.’’

Dr. Yang wasn’t shy about sharing her love for discovery.

“I don’t think I’ve ever run across anyone as enthusiastic about her work,’’ Dr. McDonald added. “She was literally jumping up and down in the hallways screaming (about the stem cells) ‘They’re beating! They’re beating!’ Her enthusiasm was contagious.’’

Armed with her degree, Dr. Yang accepted a job as resident physician in internal medicine at the University of New Mexico School of Medicine in Albuquerque. She expects to be there at least three years, but could stay longer if needed: Heart disease is the leading cause of death in New Mexico, according to the state’s Department of Health. When not working, Dr. Yang will devote time to her other passions: cooking, hiking and biking, tennis, and working out at the gym.

Dr. McDonald expects big things from his former colleague, and has no reservations about asking her to return to Tampa: “I’d like to see her career blossom and recruit her to come back to USF.’’

For more on the USF Heart Institute, visit: https://health.usf.edu/medicine/heart-institute

Written by Kurt Loft

A USF Health preclinical study suggests that kappa-opioid antagonists offer a potential treatment to help alcohol-dependent patients cut back or quit drinking

TAMPA, Fla. (March 9, 2022) — As heavy or frequent alcohol use escalates, some people continue to drink despite increasingly negative consequences such as poor job or school performance, unraveling family or personal relationships and declining physical health.

Impaired working memory, a common problem for those with alcohol use disorder (AUD), can interfere with recovery and disease management, and contribute to the risk of relapse. Working memory is one of the processes of executive function, a set of high-level mental skills (also encompassing flexible thinking and self-control) needed to learn and to manage daily life.

“People with severe alcohol dependence have reduced ability to make sound decisions, or good choices,” said Brendan Walker, PhD, a professor of psychiatry and behavioral neurosciences at the University of South Florida Health (USF Health) Morsani College of Medicine. “They ignore the problems created by excessive drinking and give up things of importance to satisfy their craving to drink more.”

Dr. Walker studies the biological brain changes that drive addictive behaviors with the aim of finding ways to improve treatment outcomes. A major obstacle to recovery, even months or years after rehabilitation and prolonged abstinence, appears to be physical changes in neurotransmitters and their receptor targets as the brain adapts to abuse of alcohol or other drugs.

Dr. Walker’s laboratory and others have focused on the interaction of alcohol-induced “feel bad” brain peptides (neurotransmitters) known as dynorphins that bind with kappa-opioid receptors (KORs), naturally occurring receptors for opioids in brain cells.

Now, for the first time, a preclinical study led by Dr. Walker shows that dysregulated KORs in the brain’s medial prefrontal cortex region (part of the frontal lobe) contribute to working memory deficiencies in alcohol dependence. Furthermore, the researchers discovered that a compound used to block KORs (an antagonist) alleviated these working memory deficits and may help restore “normal” executive function in those with severe AUD, Dr. Walker said.

The USF Health findings were reported Jan. 20, 2022, in Addiction Biology.

Study principal investigator Brendan Walker, PhD,  a neuroscientist at the USF Health Morsani College of Medicine, studies biological brain changes that drive addictive behaviors.

“Collectively, our research is helping establish that targeting the dynorphin-KOR system could be a viable treatment strategy for managing the hallmark symptoms of alcohol dependence — increased motivation for drinking, increased negative emotional states and compromised executive function (decision-making),” said Dr. Walker, the study’s principal investigator.

Earlier preclinical studies looked at how abnormal regulation of the dynorphin-KOR system in another brain region called the amygdala increases both motivation for alcohol consumption and negative emotional states like depression and anxiety that are amplified during sudden withdrawal from drinking.

In a series of experiments, the USF Health researchers used a rat model mimicking severe human AUD, which was induced by cycles of intoxication (long-term intermittent ethanol vapor exposure) and alcohol withdrawal (exposure to air only). This group of alcohol-dependent rats was compared with two other groups: nondependent rats (a model mimicking social drinking in humans) and alcohol-naïve rats (a control group never exposed to ethanol vapor.) All were trained and tested in a working memory task (delayed nonmatching-to-sample task) involving a T-maze.

Among the key findings:

– The alcohol-dependent rat model the researchers developed proved very effective for measuring working memory deficits.

– Medial prefrontal cortex KORs in the alcohol-dependent rats were overactivated (abnormally increased) in dependence, compared to those same opioid receptors in the nondependent and alcohol-naïve rats. This dysregulation of the dynorphin-KOR system in a brain region critical for the control of working memory correlated with worse working memory performance by the alcohol-dependent rats during acute withdrawal.

– When researchers stimulated KORs in the medial prefrontal cortex of nondependent rats with a KOR agonist mimicking dynorphin, they were able to produce profound working memory deficits like those observed in alcohol-dependent rats.

– Conversely, administering KOR antagonist norbinaltophimine (nor-BNI) to block activation of the brain KORs significantly reduced alcohol-induced impaired working memory. Alcohol-dependent rats showed working memory performance comparable to the nondependent rats.

Brain slice image showing the medial prefrontal cortex (mPFC), a region critical for the control of working memory | Courtesy of Paxinos and Watson, 2005

More studies are needed, including in humans, but previous laboratory research has already shown that KOR antagonists curb the desire to excessively consume alcohol and the negative emotions that can drive self-medication with alcohol. This latest USF Health study suggests such a compound also holds promise for restoring executive function needed for people to make better decisions about their alcohol intake and improve their quality of life, Dr. Walker said.

There is “no magic bullet” for AUD, Dr. Walker emphasized, but identifying and developing one medication that alleviates multiple symptoms could make it easier for patients to cut back or quit drinking when combined with cognitive behavioral therapy.

The USF Health study was supported by a grant from the National Institute of Alcohol Abuse and Alcoholism (NIAAA).

Alcohol is one of the most common forms of substance abuse and a leading cause of preventable deaths and disease, killing nearly 100,000 Americans yearly. In 2019, almost 15 million people ages 12 and older in the U.S had alcohol use disorder, according to the NIAAA.

Research Day 2022 participants welcomed the opportunity to once again connect with health sciences scholars across USF colleges and disciplines

Video by Ryan Rossy, USF Health Communications and Marketing

Masks did not hide the smiling eyes or muffle the energetic buzz of conversations that filled the USF Tampa campus Marshall Student Center on Feb. 25 as students, postdocs, residents, faculty, and staff across all health disciplines showcased the best of their scientific work.

USF Health Research Day 2022 returned in full force as an in-person event. Last year the event coincided with the university’s closure due to the COVID-19 pandemic, so everything happened online.

USF Health Research Day 2022 award winners and others pose for an onstage photo. The event, showcasing 364 poster presentations and 12 oral presentations across multiple colleges and health sciences disciplines, was held Feb. 25, 2022, in the USF Marshall Student Center.

This year, with USF COVID protocols in place, 364 poster presentations lined the Marshall Center Ballroom in the morning. Faculty judges holding folders and touchscreen tablets moved between the aisles to chat with students eager to answer questions about their research projects.

Research Day remains the largest celebration of health sciences research collaboration across all four USF Health colleges (medicine, nursing, public health and pharmacy) as well as with colleagues in other USF colleges.

Blake Scott (facing camera), a doctoral candidate in the USF Health College of Public Health, talks about her team’s research poster titled “Leveraging Unemployment and Employment Data to Characterize the Long-Term Economic Impacts of Florida’s Most Recent Category 5 Hurricane.” Scott was one of 12 students and scholars across USF Health selected to present their research at the 12th Annual Joseph Krzanowski, PhD, (Prof. Emeritus) USF Health Invited Oral Presentations.

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“It’s so wonderful to be back!” said Blake Scott, a doctoral candidate at the USF Health College of Public Health. “You just don’t get the same networking experiences when everything is virtual.”

Blake participated in her first Research Day in 2020, pre-COVID. Now, she was back sporting a flowered mask — one of 12 individuals selected to give oral presentations of their research later that afternoon. Leveraging unemployment and employment data, she led a project characterizing the long-term effects on the health and well-being of Florida Panhandle communities impacted by Hurricane Michael (a category 5 storm).

“This is a great opportunity to broaden your mind and learn about all the research collaborations here, including in colleges and disciplines outside your own,” Blake said.

Robert Deschenes, PhD, chair of the USF Health Morsani College of Medicine’s Department of Molecular Medicine (facing camera), speaks with Diptaraj Chaudhari, PhD, a postdoctoral fellow in the MCOM Department of Neurosurgery and Brain Repair, about the poster “Broad metagenomic analyses for developing clinically applicable microbiome scores.”

Second-year medical student Matthew Udine, who also delivered an oral presentation later in the day, echoed Blake’s enthusiasm.

“The personal connections make a big difference when we all gather together for Research Day,” Udine said. “You interact more with colleagues and judges, get to explore ideas with people in diverse fields, and learn more than with an online format.”

Udine’s project compared basic metabolic health indicators collected from a pre-COVID-19 cohort of first year-students from Japan’s Gifu University (Class of 2019) with the same indicators from a statistically comparable cohort of incoming students screened during the COVID pandemic (Class of 2020). The analysis showed that indicators such as systolic blood pressure, LDL cholesterol and triglycerides significantly increased in the Gifu COVID cohort. Udine and his fellow medical student team members suggested that stress, reduced physical activity, substance use and poorer diets may have influenced alterations in Japanese college students’ metabolic markers during the pandemic’s extended lockdowns.

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Stephen B. Liggett, MD, associate vice president for research at USF Health and the vice dean for research at the Morsani College of Medicine (at podium), introduces Litsa Kranias, PhD, of the University of Cincinnati (on screen), the keynote speaker for USF Health Research Day 2022. Dr. Kranias spoke on “Calcium Cycling Circuits in Cardiac Function and Survival.”

Research Day kicked off with the Annual Roy H. Behnke, MD, Distinguished Lectureship featuring speaker Litsa Kranias, PhD, Hanna Professor and Director of Cardiovascular Biology at the University of Cincinnati.

Dr. Kranias was the former chair of the Department of Pharmacology and Systems Physiology at Cincinnati and continues to play a major role in training the next generation of scientists, particularly as a mentor to women in science. She delivered her presentation, “Calcium Cycling Circuits in Cardiac Function and Survival,” via Microsoft Teams, appearing on a big screen suspended above the stage in the Marshall Student Center’s Oval Theatre.

Calcium cycling refers to the release and reuptake of intracellular calcium ions that drive muscle relaxation and contraction. In heart failure, calcium cycling is severely altered, leading to impaired contractions and deadly arrythmias (irregular heartbeats).

USF Health’s Christian Bréchot, MD, PhD,  listens to the Research Day 2022 keynote speaker in the Marshall Center’s Oval Theatre.

Throughout her National Institutes of Health-funded career Dr. Kranias has worked to better understand the complex network of proteins contributing to the heart’s function. She has focused on defining how the cardiac protein phospholamban (PLN) helps control the calcium cycling needed for hearts to work properly. Using genetically altered mouse models her laboratory demonstrated that, rather than stimulating contractility, PLN inhibited cardiac function during heart failure and this inhibition was relieved when the molecule was phosphorylated under β-agonist stimulation. PLN-deficient mice showed improved heart muscle performance without changes in heart rate.

“A major challenge of heart failure is the aberrant handling of calcium,” Dr. Kranias said. “If we can effectively inhibit PLN, we may have promising new therapeutics for heart failure.”

Kranias and colleagues discovered that PLN does not act alone. The molecule is part of a dynamic system of many proteins — including HAX-1 (an anti-cell death protein), heat shock protein 20 (HSP20) and protein phosphatase 1 (PP1), to name just a few — which interact to regulate PLN activity and the muscle cell contractions that make the heart pump.

Dr. Kranias and collaborators also found that inhibiting PP1 can enhance cardiac function and suppress progression of heart failure. Their rigorous translational research, moving from the laboratory bench to small and large animal models, helped lead to a first study in humans. This ongoing Phase 1 clinical trial is testing whether a gene therapy, which aims to activate protein phosphatase inhibitor 1 (called I-1c), can improve heart function in patients with congestive heart failure.

Matthew Udine, a second-year medical student,  gives an oral presentation during USF Health Research Day 2022. He led a project titled “Changes in basic metabolic health of first-year Japanese college students due to the Covid-19 pandemic.”

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Research Day culminated with an Awards Ceremony announcing the winners in 29 competitive categories – including 18 monetary awards totaling $8,600.

For the list of Research Day 2022 award winners, click here.

For the list of Research Day judges and sponsors, click here.

For the full presentation by Research Day keynote speaker Litsa Kranias, PhD, click here.

More photos

Photos by Allison Long, USF Health Research Communications and Marketing

Students chat with peers and faculty about their research in the USF Marshall Student Center Ballroom as they wait for the poster presentation judging.

Caitlin Wolfe, a PhD candidate in the USF Health College of Public Health, works on her laptop in front of her poster about vaccine hesitancy, shortly before the judging begins for USF Health Research Day 2022.

Estelle Toto Lobe (left), a fourth-year biomedical engineering student at the USF College of Engineering, explains her research poster to Laura Blair, PhD, assistant professor in the MCOM Department of Molecular Medicine.

Douglas Haladay, DPT, PhD, (left) associate dean and school director of of Physical Therapy & Rehabilitation Science, and Haru Okuda, MD, executive director of USF Health’s Center for Advanced Medical Learning and Simulation (CAMLS), check their notes between judging posters.

Research Day participants, flashing the “Go Bulls” sign, pose for a group photo before setting up their poster presentations.

Hariom Yadav, PhD, of the USF Center for Microbiome Research, and Ji Li, PhD, of the USF Health Heart Institute  — Photos by Allison Long, USF Health Communications

Two researchers from the USF Health Morsani College of Medicine have received Florida Department of Health (FDOH) grants to help advance discoveries in Alzheimer’s disease and in tobacco-related heart disease.

Hariom Yadav, PhD, an associate professor of neurosurgery and brain repair and director of the USF Center for Microbiome Research, was awarded total expected funds of $743,661 over four years from the FDOH Ed and Ethel Moore Alzheimer’s Disease Research Program. The multidisciplinary consortium project is titled “Role of Microbiome in the Aging of Gut and Brain in Floridian Older Adults.”

Researchers at USF and several other sites across Florida will study how diet affects the gut and oral microbiomes linked to brain health in adults ages 60 and older. Age is a key risk factor for Alzheimer’s disease and related dementias (ADRD); no effective treatment exists, and early risk detection remains a challenge. The FDOH-supported research seeks to determine whether unique microbiome signatures can differentiate older adults suffering cognitive decline and ADRD from their healthy counterparts and predict disease progression. The study will also examine whether abnormalities in microbe-derived metabolites, excessive gut “leakiness” and inflammation definitively contribute to cognitive impairment and ADRD—with the ultimate aim of identifying measures to prevent or delay these devastating conditions.

Ji Li, PhD, professor of surgery and a member of the USF Health Heart Institute, was awarded total expected funds of $583,200 over three years from the FDOH James and Esther King Biomedical Research Program. The grant is titled “Sirtuin 1 and Cardiovascular Impairment by Cigarette Smoking.”

Dr. Li’s laboratory has shown that the anti-aging protein sirtuin 1 (SIRT1) plays a role in cardiovascular disease development, and emerging evidence suggests that SIRT1 is a component of signaling pathways that allow cells to sense and react to cigarette smoking. The FDOH-supported preclinical project will test whether and how SIRT1 signaling helps control the harmful effects of cigarette smoking on the heart’s pumping function in hypertension (abnormally high blood pressure). The study’s outcome could lead to the discovery of SIRT1 agonists or other drugs that may reduce damage and death from hypertensive heart disease associated with chronic smoking.

USF Health-UT Southwestern Medical Center preclinical study suggests inhibiting PPP1R3G/PP1γ may protect against tissue damage from heart attacks, other diseases linked to inflammation

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TAMPA, Fla. (Feb. 16, 2022) – Cell death plays an important role in normal human development and health but requires tightly orchestrated balance to avert disease. Too much can trigger a massive inflammatory immune response that damages tissues and organs. Not enough can interfere with the body’s ability to fight infection or lead to cancer.

Zhigao Wang, PhD, associate professor of cardiovascular sciences at the University of South Florida Health (USF Health) Morsani College of Medicine, studies the complex molecular processes underlying necroptosis, which combines characteristics of apoptosis (regulated or programmed cell death) and necrosis (unregulated cell death).

During necroptosis dying cells rupture and release their contents. This sends out alarm signals to the immune system, triggering immune cells to fight infection or limit injury. Excessive necroptosis can be a problem in some diseases like stroke or heart attack, when cells die from inadequate blood supply, or in severe COVID-19, when an extreme response to infection causes organ damage or even death.

A new preclinical study by Dr. Wang and colleagues at the University of Texas Southwestern Medical Center identifies a protein complex critical for regulating apoptosis and necroptosis — known as protein phosphatase 1 regulatory subunit 3G/protein phosphatase 1 gamma (PPP1R3G/PP1γ, or PPP1R3G complex). The researchers’ findings suggest that an inhibitor targeting this protein complex may help reduce or prevent excessive necroptosis.

The study was reported Dec. 3, 2021, in Nature Communications.

Zhigao Wang, PhD, associate professor of cardiovascular sciences, in his laboratory at the USF Health Heart Institute. Images on the monitor depict two types of cell death: apoptosis (left) and necroptosis. — Photo by Allison Long, USF Health Communications

“Cell death is very complicated process, which requires layers upon layers of brakes to prevent too many cells from dying,” said study principal investigator Dr. Wang, a member of the USF Health Heart Institute. “If you want to protect cells from excessive death, then the protein complex we identified in this study is one of many steps you must control.”

Dr. Wang and colleagues conducted experiments using human cells and a mouse model mimicking the cytokine storm seen in some patients with severe COVID-19 infection. They applied CRISPR genome-wide screening to analyze how cell function, in particular cell death, changes when one gene is knocked out (inactivated).

Receptor-interacting protein kinase (RIPK1) plays a critical role in regulating inflammation and cell death. Many sites on this protein are modified when a phosphate is added (a process known as phosphorylation) to suppress RIPK1’s cell death-promoting enzyme activity. How the phosphate is removed from RIPK1 sites (dephosphorylation) to restore cell death is poorly understood. Dr. Wang and colleagues discovered that PPP1R3G recruits phosphatase 1 gamma (PP1γ) to directly remove the inhibitory RIPK1 phosphorylations blocking RIPK1’s enzyme activity and cell death, thereby promoting apoptosis and necroptosis.

Dr. Wang (back) and laboratory associate Ken Chen. — Photo by Allison Long, USF Health Communications

Dr. Wang uses the analogy of a car brake help explain what’s happening with the balance of cell survival and death in this study:  RIPK1 is the engine that drives the cell death machine (the car). Phosphorylation applies the brake (stops the car) to prevent cells from dying. The car (cell death machinery) can only move forward if RIPK1 dephosphorylation is turned on by the PPP1R3G protein complex, which releases the brake.

“In this case, phosphorylation inhibits the cell death function of protein RIPK1, so more cells survive,” he said. “Dephosphorylation takes away the inhibition, allowing RIPK1 to activate its cell death function.”

The researchers showed that a specific protein-protein interaction – that is, PPP1R3G binding to PP1γ — activates RIPK1 and cell death. Furthermore, using a mouse model for “cytokine storm” in humans, they discovered knockout mice deficient in Ppp1r3g were protected against tumor necrosis factor-induced systemic inflammatory response syndrome. These knockout mice had significantly less tissue damage and a much better survival rate than wildtype mice with the same TNF-induced inflammatory syndrome and all their genes intact.

Overall, the study suggests that inhibitors blocking the PPP1R3G/PP1γ pathway can help prevent or reduce deaths and severe damage from inflammation-associated diseases, including heart disease, autoimmune disorders and COVID-19, Dr. Wang said. His laboratory is working with Jianfeng Cai, PhD, a professor in the USF Department of Chemistry, to screen and identify peptide compounds that most efficiently inhibit the PPP1R3G protein complex. They hope to pinpoint promising drug candidates that may stop the massive destruction of cardiac muscle cells caused by heart attacks.

The research was supported by grants from the Welch Foundation and the National Institute of General Medical Sciences, a part of the National Institutes of Health.

Graphic created with Biorender app by Zhigao Wang, USF Health Heart Institute.

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.”

USF Health research discovers APC limits heart damage by preventing excessive loss of endothelial protein C receptors on the cardiac muscle cell membrane

TAMPA, Fla. (Jan. 31, 2022) — A University of South Florida Health (USF Health) preclinical study offers molecular insight into how activated protein C (APC) may improve aging patients’ tolerance to reperfusion injury – a potentially adverse effect of treatment for ischemic heart disease.

The research, published online Dec. 21 in Circulation Research, suggests that drugs derived from APC may limit ischemia and reperfusion-induced heart damage (reperfusion injury for short) and thereby help preserve cardiac function in older hearts.

Advanced age is a major risk factor for ischemic heart disease, often caused by a buildup of plaques in coronary arteries that narrows the vessels and restricts the supply of oxygenated blood to the heart. This “hardening of the arteries” can eventually trigger a heart attack.

Blood thinners, clot-buster medications, and other drugs, as well as procedures such as coronary artery bypass surgery and balloon angioplasty, are commonly used to restore blood flow to oxygen-starved (ischemic) heart muscle tissue. Paradoxically, especially in older patients, these necessary revascularization treatments can worsen cellular dysfunction and death around the site already damaged by a heart attack, or coronary artery disease. No effective treatments currently exist to prevent age-related reperfusion injury.

“Our research focuses on trying to determine why older hearts are at greater risk for reperfusion injury than younger hearts,” said lead author Di Ren, PhD, a research associate in the Department of Surgery, USF Health Morsani College of Medicine. “Our goal is to find targeted therapeutic strategies to help older people improve their resistance to the pathological condition of ischemia and reperfusion stress.”

“The preliminary evidence in this paper suggests that treatment with activated protein C has the potential to strengthen the cardiac tolerance of aging patients to reperfusion injury from surgery, minimally invasive procedures, or drugs, and (thereby) increase heart attack prevention or survival,” said the study’s principal investigator Ji Li, PhD, a professor of surgery at the USF Health Heart Institute.

Di Ren, PhD, a research associate in the USF Health Department of Sugery, was the Circulation Research paper’s lead author.

APC, a protein circulating in blood, has both anticoagulant (blood clot prevention) and anti-inflammatory functions that can help protect cells from disease and injury. Endothelial protein C receptor (EPCR) – located both on cells lining blood vessels and on the surface of cell membranes, including heart muscle cells – is associated with increased APC production and regulates APC’s subsequent cell signaling (or cell communication).

In this mouse model study, the researchers analyzed how APC exerts cardiac protection during ischemia and reperfusion. The groups of mice observed included young and old “wild-type” mice with all their genes intact, and young “knock-in” EPCR R84A/R84A mice genetically modified to make their EPCR receptors incapable of interacting with the APC protein as well as their wild-type littermates without the EPCR R84A/R84A mutation.

Naturally occurring APC or one of two laboratory-engineered APC derivatives were administered to the mice with heart attack-induced ischemia before reperfusion. One derivative (compound APC-2Cys) selectively activated a signaling pathway to promote cell protection without inhibiting blood clotting (coagulation). The other derivative (compound APC-E170A) selectively triggered a signaling pathway promoting only anticoagulation.

Ji Li, PhD, a professor of surgery at the USF Health Heart Institute, was the study’s principal investigator. — Photo by Allison Long, USF Health Communications

Among the team’s key preclinical findings:

— The stress of Ischemia and reperfusion injury induced “shedding” of EPCRs in young and old wild-type mice – that is, a greater number of these receptors were cut from the heart muscle cell membrane and then moved into the bloodstream. This EPCR shortage (deficiency) in the heart can impair activated protein C signaling critical for favorably regulating energy metabolism and anti-inflammatory responses, preventing cell death, and stimulating other activities needed to protect cardiac muscle cells.

— While the hearts of the old and young wild-type mice both showed EPCR shedding, older hearts experienced a more severe EPCR deficiency and decline in APC signaling activity in response to reperfusion injury. No APC signaling was detected in the EPCRR84A/R84A mice, because APC was blocked from binding to the cell membrane receptor.

— Administering APC or its derivatives helped reduce heart damage inflicted by ischemia and reperfusion, particularly in the old mice. Digging deeper, the researchers discovered that by stabilizing (maintaining) EPCR on the cardiac cell membrane, APC strengthens the aging heart’s resistance both to heart attack-related ischemia and to injury associated with restoring coronary artery blood flow.

— Furthermore, APC and the APC-2Cys signaling derivative, but not the APC-E170A anticoagulant-selective signaling (a potential bleeding risk), helped preserve cardiac function. All cardioprotective effects of APC were weaker in young mice in which EPCR was eliminated; their hearts looked and performed like that of older mice.

— The researchers detailed how APC treatments improve cardiac function by regulating both acute (short-term) and chronic (longer-term) metabolic pathways. They demonstrated that enzyme AMPK (AMP-activated protein kinase) mediates an acute adaptive response to cardiac stress immediately following heart attack, while enzyme AKT (protein kinase B) regulates chronic metabolic adjustments to reperfusion stress over time. APC treatment led to better enzyme activity and more efficient energy balance needed to contract cardiac muscle cells and pump blood from the heart to the rest of the body.

“APC is beneficial for ischemia-reperfusion injury both in the acute and chronic stages, so appropriate APC derivatives might be used both as preventive and therapeutic drugs,” Dr. Li said.

Activated protein C (green) interacts with endothelial protein C receptors (red) to form APC/EPCR binding complex (yellow) and stabilize subsequent EPCR-regulated signaling in heart muscle cells under hypoxia-reperfusion stress.  Image courtesy of Ji Li Laboratory, USF Health; first appeared in Circulation Research; DOI: 10.1161/CIRCRESAHA.121.319044

The USF Health Heart Institute researchers collaborated with scientists from Scripps Research Institute, McMaster University (Canada), and the Oklahoma Medical Research Foundation.

Their work was funded by grants from the National Institutes of Health, both the NIGMS and NHLBI.