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Three students from United States military academies have completed biomedical research summer internships at OMRF. Two students from the U.S. Naval Academy in Annapolis, Md., and one from the U.S. Air Force Academy in Colorado Springs, Colo., participated in the foundation’s ninth annual John H. Saxon Service Academy Summer Research Program. Oklahoma City native and Heritage Hall High School graduate Paige Miles is a midshipman at the U.S. Naval Academy. She worked in the lab of Courtney Griffin, Ph.D., studying blood vessel development. “Both of my parents are doctors in Oklahoma City, so when I heard about this opportunity I jumped at the chance to not only get experience working in medical research but also to move home for a few weeks,” said Miles. “This has been an unbelievable opportunity, and I am so fortunate have the chance to work with a great scientist like Dr. Griffin.” Connor King, also a midshipman at the Naval Academy, investigated cell division under the guidance of researcher Roberto Pezza, Ph.D. The Suffolk, Va., native researched a protein involved in DNA recombination and its function in cell development. “I have a pre-medical focus, and this experience has had a big impact on me because it shows the lifetime of research and work that goes into making each of these discoveries,” said King. “It really changes your perspective on the value of research science.” Finally, U.S. Air Force Academy cadet Lionel Gumireddy studied the impact of diabetes on the heart with OMRF scientist Kenneth Humphries, Ph.D. Gumireddy worked on an enzyme that has been linked to diabetes. “I’ve learned even more than I expected, and I have loved every minute of the experience,” said Gumireddy, a Pittsburgh, Pa., native. “I’m trying to be a doctor in the Air Force, and I’m leaning toward critical care transport. This introduction to the research side of medicine has been eye-opening.” Muskogee physician John Saxon, III, M.D., established the program to honor his late father, a West Point graduate and Air Force pilot. “This exposure to real-world medical research is invaluable to the students, and it also adds needed help and fresh perspectives in our labs,” said OMRF Senior Human Resources Specialist Heather Hebert, who coordinates the program. “We’re grateful to Dr. Saxon for supporting this unique program.” |
Discovery could help treat Tylenol overdoses
Acetaminophen, sold over the counter as Tylenol, is one of the world’s most widely used pain relievers. But too much of the drug can lead to serious liver damage.
Now, new research from OMRF has pinpointed the cause of liver bleeding during acetaminophen overdose. OMRF scientists have also discovered a new potential treatment for the condition, which often strikes users of Percocet and Vicodin, pain medications that also contain acetaminophen.
OMRF scientists Courtney Griffin, Ph.D., and Siqi Gao discovered that a marked increase in the activity of an enzyme called plasmin caused liver bleeding in the event of acetaminophen overdose.
“It was well known that acetaminophen, like most drugs, is metabolized in the liver. When you get too much of it, toxic byproducts start to build up and can damage liver cells,” said Gao, who is also a Ph.D. student at the University of Oklahoma Health Sciences Center. “It was also known that a lot of plasmin is generated in acetaminophen overdose, but it wasn’t clear why.”
Griffin and Gao broke new ground by making a connection between plasmin activity and liver bleeding following acetaminophen overdose. While this finding is important on its own, Griffin said, the OMRF researchers also made a related discovery that yielded important treatment options for overdose patients.
In laboratory mice, the scientists were able to reduce plasmin levels through treatment with tranexamic acid, a prescription medication used to prevent excess blood loss from major trauma or surgeries.
“If the plasmin is breaking down the blood vessels and causing them to rupture, this can help dampen that effect to prevent excessive bleeding,” said Griffin.
In humans, it’s possible that treating this bleeding with tranexamic acid could help facilitate liver recovery from an overdose and also lessen the damage, said Griffin. “We think it can certainly protect against the bleeding itself, but its role in overall liver recovery is still unknown. That’s the next step for this work.”
The treatment impact of the findings could be significant, said Griffin, especially since tranexamic acid has already been approved by the Food and Drug Administration for another condition.
“It could be administered soon after a patient arrives at the hospital,” she said. “We are excited to see where the next stage takes us.”
The new findings were published in the journal Hepatology. OMRF researchers Florea Lupu, Ph.D., and Robert Silasi-Mansat, Ph.D., also contributed to the findings. This work was supported by grant No. P30GM114731 from the National Institute of General Medical Sciences, a part of the National Institutes of Health.
OMRF discovers new approach to treating obesity
Scientists at OMRF have discovered a new protective mechanism against obesity and insulin resistance, which contributes to type 2 diabetes.
The findings could potentially lead to new drugs to help weight loss or combat obesity and associated metabolic disorders.
In a new study, the OMRF scientists used genetically modified mice that do not produce an enzyme that plays a critical role for maintenance and repair in the mitochondria, a powerhouse of cells responsible for converting food to energy.
The mice without the enzyme had supercharged fat metabolism and stopped gaining weight, even when researchers put the rodents on a high-fat diet. The mice also didn’t show signs of insulin resistance, which accompanies obesity and typically leads to type 2 diabetes.
Scientist Deepa Sathyaseelan, Ph.D., now a faculty member at the University of Oklahoma Health Sciences Center and OMRF affiliate, led the research.
“I think it’s important to understand what mediates insulin resistance because that’s a root cause of diabetes,” said OMRF scientist Kenneth Humphries, Ph.D., who contributed to the study. “You have to understand what causes insulin resistance to know how to fix it, and we now know this protein has a role that was previously unidentified.”
According to the Oklahoma State Department of Health, more than 300,000 Oklahomans reported being diagnosed with diabetes. The state ranks fourth in the U.S. in diabetes mortality rate.
Gavin Pharaoh, an OMRF researcher and graduate student at OUHSC who also worked on the project, said the new research could pave the way for new drug targets to maintain proper insulin sensitivity to help control obesity and potentially prevent or treat diabetes.
“It’s exciting in the sense that it’s a novel approach for treating obesity, which is a problem that is only getting worse,” said Pharaoh. “This is a brand new mechanism of affecting the disease and could lead to some promising results down the line.”
The next step, said Pharaoh, is to screen for compounds and test to see if this same effect can be achieved through a drug instead of by altering the genes directly, allowing for development of a therapy.
The new findings appeared in the journal EMBO Reports.
OMRF researchers Shylesh Bhaskaran, Ph.D., Rojina Ranjit, Ashley Murphy, Satoshi Matsuzaki, Ph.D., Brittany Forbes, Michael Kinter, Ph.D., and Timothy Griffin, Ph.D. also contributed to the findings.
The project was funded by grants 13BGIA14670024 from the American Heart Association, A13415 from the American Federation for Aging Research, and National Institute of General Medical Sciences grant P20 GM103636, which is a part of the National Institutes of Health.
OMRF research shows how exercise can benefit cartilage
Remember the saying, “What doesn’t kill you makes you stronger?”
Timothy Griffin, Ph.D., a researcher at OMRF, has applied that old adage to the study of osteoarthritis. His lab’s recent discovery has shown how healthy types of joint-loading, as occurs with walking or jogging, are beneficial to cartilage and help protect it from breaking down over time.
Osteoarthritis, or OA, is the most common form of disability in the U.S., affecting nearly 31 million Americans. It occurs when the cartilage that cushions bones in the joints breaks down and wears away, causing inflammation and pain as the bones rub against one another. OA is most commonly found in the knees, hips, fingers, lower back and neck.
For this study, Griffin specifically looked at articular cartilage–the smooth, white tissue that covers the ends of bones where they come together to form joints–to study how it reacted at a cellular level to various forms of joint-loading.
Griffin found that healthy forms of loading generates molecules generally considered toxic to cells, which has a beneficial effect of increasing protective responses in cartilage.
“We looked at many different types of loading, such as those associated with standing and walking up to jogging with a heavy backpack all day,” said Griffin. “We found that in all situations, the physical stress on the cartilage caused the tissues to become more oxidized.”
While oxidation is generally thought to be bad, some is actually beneficial, because it sparks the body’s natural antioxidant defenses.
They found that a key antioxidant molecule called glutathione increased in one of the loading conditions, the one similar to walking. This molecule, said Griffin, is present at fairly high levels in cells throughout the body.
“It’s one of the body’s primary antioxidant molecules that can help provide a first line of defense against oxidative stress,” he said. “Having more glutathione in cartilage means there’s a greater capacity to protect against damaging loads.”
The loading conditions similar to standing or jogging with a heavy load caused even greater cartilage oxidation without the benefit of the increase in glutathione. Griffin said, “Clearly there is a sweet spot for getting the right amount and type of loading that gives cartilage the most protection.”
Our cells contain many different kinds of molecules and enzymes that protect us against oxidative stress. One of the key findings, said Griffin, is that now they better understand how exercise helps to keep our joints healthy.
“This tells us that we need to think more about the pathways that regulate the production of glutathione to see how they could be harmed with obesity, aging, and other conditions that increase the risk of osteoarthritis,” he said, adding that this information could also be useful in the future for thinking about potential metabolic supplements or genetic engineering strategies that could help prevent joint damage.
The data was published in the Journal of Orthopaedic Research. OMRF scientist Mike Kinter, Ph.D., also contributed to the findings.
This research was funded by grants from the National Institutes of Health, Arthritis National Research Foundation, Arthritis Foundation and the Oklahoma Center for the Advancement of Science and Technology.
AHA, OMRF host STEM event for teen girls
On Sunday, the American Heart Association hosted a special STEM education program for its 2017-18 class of Sweethearts at OMRF.
Women representing a variety of science, technology, engineering and math fields met face-to-face with participants in small groups before coming together in a general session. Panelists fielded questions from attendees and further expanded on their personal experiences in the sciences, both in school and as they established their careers.
OMRF scientist Courtney Griffin, Ph.D., served as host for the event. Griffin has spent her career manipulating DNA, the encyclopedia of genetic information that is inside of each of our cells. In the lab, she edits DNA of laboratory mice so that she can understand the development and function of blood vessels in these animals. The AHA has funded her research for more than 20 years.
Other speakers were OMRF physician-scientist Eliza Chakravarty, M.D., OMRF statistical geneticist Courtney Montgomery, Ph.D., Angela Robinson, Senior Business Manager at The Boeing Company, and Usha Turner, Director of Environmental Affairs at OGE Energy Corp.
Each of the women described the nature of her education and career path and her current work. They also told what they would like to have said to themselves at the age of 16 about perseverance, enlisting mentors and goal-setting.
“This STEM event is exciting for me, because it unifies the strengths of AHA and OMRF in promoting science and math career options to young women,” said Griffin. “I might not have considered becoming a scientist if I hadn’t met an influential female scientific role model when I was a teenager. I hope I can similarly inspire young women to consider science as a rewarding and creative career option.”
AHA’s Sweetheart Program provides educational and social programs for the girls during the school year. Activities are designed to groom the Sweethearts as future heart health advocates. The girls are presented at the annual Heart Ball in February.
“The girls were eager to know what it’s like to work in male-dominated fields and how STEM leaders are able to juggle family life along with such demanding careers,” said American Heart Association Executive Director Debbie Hite Stewart. “The event really seemed to provide an opportunity for the students to think about their futures and what direction they may want to go as they near high school graduation.”
OMRF researchers identify gene mutation present in pair of diseases
Scientists at OMRF have discovered how mutations in one specific gene can cause two distinct and rare diseases.
OMRF researcher Lorin Olson, Ph.D., studies a protein signal called platelet-derived growth factor (PDGF), which plays a key role in the body’s ability to repair wounds. But too much PDGF promotes fibrosis and inflammation, making proper balance key. Olson’s research focuses on understanding how PDGF works.
In a new paper published in the journal Genes and Development, Olson and his team have shown how too much PDGF causes disease. Specifically, they’ve found how mutations in PDGF receptor beta (PDGFRB) can trigger two rare diseases, Penttinen syndrome and Kosaki overgrowth syndrome.
“Typically, mutations in the same gene are predicted to have the same outcome,” said Olson. “So we were puzzled by reports that two unique diseases were coming from the same mutant gene.”
Penttinen syndrome is characterized by the appearance of premature aging. The condition can also result in age-related problems like osteoporosis, facial deformity and bone defects like scoliosis. Kosaki overgrowth syndrome can lead to skeletal overgrowth, fragile skin and facial deformity.
Using mouse models, Olson was able to show that the diseases caused by PDGFRB mutations are largely determined by a modifying gene called STAT1. When STAT1 was present along with a PDGFRB mutation, it led to the appearance of premature aging in mice, similar to what happens in Penttinen syndrome in humans. On the other hand, if a PDGFRB mutation occurred in the absence of STAT1, they saw overgrowth in mice similar to symptoms of Kosaki overgrowth syndrome.
As a result, Olson and his lab were able to pinpoint STAT1 as a determining factor in which disease results from mutations in the PDGFRB gene.
“Humans aren’t likely to be missing STAT1 altogether, or they would have a host of other problems,” said Olson. “But there may be strong or weak versions of this gene in humans that are affecting the consequence of the PDGFRB mutation. By understanding STAT1 and what can happen when it’s over-activated or inactivated, it might suggest new ways to treat these diseases.”
Olson said drugs already exist that inhibit PDGFRB mutations, as well as others that work on the STAT1 pathway, so these findings open the door to more treatment options and a launching point to pursue future therapies.
Olson came to OMRF from the Mt. Sinai School of Medicine in New York, New York, in 2010. He received his Ph.D. from the University of California, San Diego, and now is an associate member in OMRF’s Cardiovascular Biology Research Program.
Other OMRF researchers who contributed to the findings were Shayna Medley, Jang Kim, Chengyi Sun, Ph.D., Hae Ryong Kwon, Ph.D., Hiromi Sakashita, Ph.D., Yair Pincu, Ph.D., Longbiao Yao, M.D., and Timothy Griffin, Ph.D. Other former OMRF scientists involved in the work were Chaoyong He, Ph.D., and Danielle Eppard.
National Institutes of Health grants that helped to fund this research include P20GM103636 from the National Institute of General Medical Sciences and R01AR070235 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. This research was also supported by additional funds from the Oklahoma Center for Adult Stem Cell Research, a program of TSET, and the Pew Charitable Trusts.
Can you control your family’s genetic destiny?
As the parent of two children, Courtney Griffin, Ph.D., is well aware that the choices she and her husband make will have a profound impact on their daughters’ lives.
But Griffin is also a scientist at the Oklahoma Medical Research Foundation who studies the emerging field of epigenetics. And through her research in this area, she is learning that the decisions we make as parents—what we feed our children, how much attention we give them as infants—may impact more than just our children, but also the genetic destinies of our descendants for generations to come.
Epigenetics are chemical changes to the genome that affect how DNA is packaged and expressed without affecting the underlying genetic sequence.
“Epigenetics works like a watermark on top of genes,” said Griffin. “If you imagine your genetic makeup as a well-oiled machine, epigenetics are like the rust that settles on it and leaves a surface coating. This can muck things up, suppressing genes that need to work or turning on genes that are meant to be quiet.”
Scientists have determined that these marks can form as a result of the foods we eat, the toxins we ingest or even the stressful events we experience. And that they can persist for generations in some species.
“The real news with epigenetics is that these actions can theoretically affect more than just you and your children, but also your great grandchildren, great-grandchildren and beyond,” said Griffin.
A geneticist by trade, Griffin has spent her career manipulating DNA, the encyclopedia of genetic information that is inside of each of our cells. Griffin edits DNA of laboratory mice so that she can understand the development and function of blood vessels in these animals. She said her experience has shown her that epigenetic marks really can serve to reprogram genes’ behavior.
“Anything that genetics controls, which is essentially everything about us, can be altered,” said Griffin. “It comes back to how the marks are read by proteins in the cell. Any extra variable changes what they read, and these variables can be introduced by bad lifestyle habits.”
Luckily, said Griffin, research suggests these epigenetic marks don’t have to be permanently etched onto your DNA. “It appears these marks are quite malleable in humans, and making healthy choices like eating a better diet or reducing stress can make a difference,” she said.
“To me, it’s profound and empowering that we can influence how our genes work through the choices we make,” she said. “It gives us yet another reason to live a healthy life and make smart choices, because it doesn’t just affect us.”
Military academy students get hands-on lab experience at OMRF
Three U.S. military academy students have completed a crash course in biomedical research at OMRF through the John H. Saxon Service Academy Summer Research Program.
Two students from the U.S. Naval Academy in Annapolis, Md., and one from the U.S. Air Force Academy in Colorado Springs, Colo., participated in the foundation’s eighth annual program.
John Saxon III, M.D., a Muskogee physician and OMRF board member since 2000, established the program to honor his father, a West Point graduate who taught for five years at the U.S. Air Force Academy and was a career Air Force pilot before passing away in 1996.
The Saxon program is designed to provide military academy students with an opportunity to work side-by-side with OMRF’s senior scientists.
Matthew Lerdahl, a Coon Rapids, Minn., native and cadet captain first class in the U.S. Air Force, worked in the lab of Roberto Pezza, Ph.D., studying cell division.
Lerdahl, a biology major, specifically worked on what happens when cell division goes wrong in mitosis, which can result in disorders like Down syndrome and is implicated in certain cancers.
“This experience has been even more intense than I thought, and that’s a great thing. It’s very hands-on and the mentors are super helpful but also give you the freedom to make mistakes and learn on your own,” said Lerdahl. “It made me a better scientist and researcher. The environment here is just phenomenal.”
Erin McShane, a battalion sergeant major at the U.S. Naval Academy, is a chemistry major who was assigned to the lab of Ken Humphries, Ph.D., where she worked with an enzyme called PFK2. This is important because it is under-expressed in people with diabetes. It could provide a clue as to why diabetics can’t properly metabolize glucose.
“This project has been fascinating and a truly unique experience. I have an interest in serving in the Navy’s medical corps, and this has provided invaluable exposure to what medical research looks like up close,” she said. “We have sent someone from the academy here for several years, and I am thrilled to have had this amazing opportunity.”
Yuma, Ariz., native and Naval Academy midshipman second class Jocelyn Rodriguez worked under the guidance of Courtney Griffin, Ph.D., where she studied the formation of the vasculature, specifically during development of embryos. Rodriguez, who studies chemistry, said understanding how vessels work is important not only for embryonic development but also during the development of a tumor. Understanding how to disrupt the process could lead to new ways to slow or stop tumor growth.
“I have an interest in becoming a medical officer, and this opportunity has been great for my future,” she said. “It’s fun to pick the scientists’ brains to see if I want to do research or be more on the clinical side of things. It’s also great to see the leadership styles here at OMRF. Dr. Griffin is phenomenal and you can really see people love to come to work every day in her lab. It’s inspiring.”
Investigating the role of obesity in arthritis
Research from OMRF has revealed new findings on the effects of obesity and on fat tissue in the knee joint in the formation of osteoarthritis, the most common form of arthritis.
Osteoarthritis, or OA, is the most common form of disability in the U.S., affecting nearly 27 million Americans. It occurs when the cartilage that cushions bones in the joints breaks down and wears away, leaving the bones to painfully rub against one another. This is most commonly found in the knees, hips, fingers, lower back and neck.
To better understand disease onset, OMRF researchers Tim Griffin, Ph.D., and Erika Barboza Prado Lopes, Ph.D., looked at fat tissue in the knee joint known as the infrapatellar fat pad. Their research centered on whether a high-fat diet causes the fat pad in the knee to become inflamed, which then contributes to the formation of OA.
“Obesity, particularly from excess abdominal fat, causes a low level of inflammation throughout the body that is thought to increase the risk of osteoarthritis in the knee,” said Griffin. “We used that knowledge to ask a more specific question: Is the knee fat pad itself also a source of inflammation with obesity that is part of this increased risk of osteoarthritis?”
In order to find the answer, the scientists took a step back in the research process. Griffin said they already knew they could feed mice a high-fat diet and cause OA of the knee. But they needed to study what happened in the fat pad under the conditions of a high-fat diet before OA develops to know if it could be causing the disease. This study, Griffin said, was one of the first of its kind to look at the fat pad in a pre-disease stage.
“We started far enough into the diet where we could see inflammation in the abdominal fat, but not so far that the cartilage became damaged in the knee,” said Griffin. “This let us look at the early changes happening in the joint but not at the stage where there is full-on osteoarthritis.”
The researchers made an unexpected discovery: Obesity increased the size of the knee fat pad without causing it to become inflamed.
Because the fat pad in the knee did not become inflamed with the high-fat diet, the researchers do not believe it is initiating the increased risk of OA. But it may still play a role in overall joint health, said Lopes.
According to Lopes, studies like this may ultimately hold the key to developing new therapies for osteoarthritis. “We have to understand the basic mechanisms at work and ask questions about how each tissue in the joint contributes to the overall health of the joint. Perhaps the increase in fat pad size without the inflammation is a protective response. This answer isn’t what we anticipated, but it helps push us in the right direction.”
The new findings have been published in the journal Arthritis & Rheumatology.
OMRF researchers Florea Lupu, Ph.D., Susan Kovats, Ph.D., and Rheal Towner, Ph.D., also contributed to the research, which was supported by grants from the National Institutes of Health (numbers P20-RR-018758, P20-GM-103441 and R03-AR-066828) and the Arthritis Foundation.
OMRF receives federal grant to investigate cell death
An OMRF scientist has received a four-year federal grant to investigate the biological process of cell death.
The grant, awarded by the National Heart, Lung, and Blood Institute, will provide $1.74 million to OMRF scientist Courtney Griffin, Ph.D., to study what triggers a form of cell death called necroptosis in the vascular system.
The body uses programmed cell death to carry out specific biological purposes. “It’s an important and essential part of some phases of human development,” said Griffin. “For example, as embryos, our hands look like little round paddles until programmed cell death kills off the cells between our fingers.”
This type of cell death that destroys the cells between our fingers is called apoptosis, and it has been studied for decades. However, a newer form of cell death called necroptosis has been identified recently, and Griffin is interested in identifying the causes and effects of necroptosis in blood vessels.
While apoptosis is often seen as beneficial and orderly, necroptosis appears to be a much uglier form of cell death. In apoptosis, cells die neatly, and other cells come along to clean up behind them, said Griffin. But necroptosis results in a messy sort of cell death, which can cause inflammation and damage to nearby cells in the surrounding tissue.
One way to compare apoptosis with necroptosis is to imagine two types of building demolition, said Griffin, who joined OMRF’s scientific staff in 2008 from the University of North Carolina at Chapel Hill.
“Apoptosis is like an implosion, where the building’s walls fall inward onto themselves in a nice, controlled way,” she said. “But in necroptosis, it’s more like when a gas main blows and the building explodes outward. The damage is far greater and more widespread. Both buildings come down, but the resulting damage is vastly different.”
Griffin’s lab will study the rapidly growing blood vessels in mouse embryos to investigate not only what triggers necroptosis, but also to learn about the secondary effects of the damage imposed by this form of programmed cell death.
“Understanding the causes and effects of necroptosis on the embryonic vascular system is only the tip of the iceberg,” she said. “We hope our findings may also provide insight into how necroptosis contributes to adult vascular diseases like atherosclerosis and aneurysms.”
The grant, 1 R01 HL134778-01, is funded through the NHLBI, a part of the National Institutes of Health.
