ETSU Researcher Dr. Valentin Yakubenko Uncovers a New ‘Brake Pedal’ on Inflammation

For a college freshman, biology often feels like a collection of vocabulary words, but in the laboratory of Dr. Valentin Yakubenko at East Tennessee State University, it is a high-stakes battlefield.

Dr. Yakubenko, an associate professor in the Department of Biomedical Sciences at the Quillen College of Medicine, is leading research that could change how we treat some of the deadliest conditions in modern medicine by understanding the “brakes” on the human immune system.

At the center of Dr. Yakubenko’s work is a process everyone has experienced: inflammation. When you scrape your knee or catch a cold, your body sends a signal to your immune system to send in the troops. This is usually a good thing. However, Dr. Yakubenko explains that inflammation is also the hidden engine behind many long-term diseases, including heart disease (atherosclerosis), diabetes, and Alzheimer’s.

In a healthy response, the immune system turns on to fight and then turns off once the job is done. But in conditions like sepsis, a life-threatening overreaction to infection, the system doesn’t know when to quit. Yakubenko describes the body’s primary first responders, known as neutrophils, as “crazy warriors.” These white blood cells rush to an infection and release powerful chemical weapons called Reactive Oxygen Species (ROS). While these chemicals are great at killing bacteria, they are also “blind”; they can’t tell the difference between a germ and your own healthy organs.

Contributed/ETSU

When too many of these warriors arrive at once, they cause a “cytokine storm,” a massive wave of inflammation that can lead to organ failure and death. Dr. Yakubenko’s research focuses on finding the balance: how to keep the warriors active enough to protect us but controlled enough to keep them from destroying the body they are trying to save.

One of the most significant recent breakthroughs in Dr. Yakubenko’s lab involves a molecule called Carboxyethylpyrrole, or CPP. To understand CPP, you have to imagine how a neutrophil moves. These cells “walk” from the blood vessels into our tissues by using tiny “hands” on their surface called integrins. These integrins grab onto the tissue (the substrate) and pull the cell forward.
In a normal environment, this walking is easy. However, during intense inflammation, the “warrior” neutrophils release their chemical weapons (ROS), which actually change the chemical makeup of the ground they are walking on. This chemical reaction creates CPP.

Before this reaction, the proteins in our tissue have a positive electrical charge. CPP, however, is negatively charged. This change in charge acts like a molecular glue. When the neutrophils’ integrin “hands” touch a surface modified by CPP, they grab on so tightly that they have a hard time letting go to take another step.

“Technically, the presence of this product changes the surface charge of the proteins, and the surface becomes completely different,” Dr. Yakubenko said. By making the tissue stickier, the body creates a natural “stop sign.” This prevents too many neutrophils from flooding into a specific area, effectively acting as a biological brake to prevent a cytokine storm.

While the research happens in Johnson City, its influence reaches the most prestigious medical institutions in the world. Dr. Yakubenko’s lab has established a reputation for producing elite scientists. Two of his most recent graduate students from ETSU have already transitioned into high-level careers. One former student is currently completing a postdoctoral fellowship at Harvard Medical School, while another has moved on to conduct research at Georgetown University.

The legacy of success is continuing with current lab members. Jared Casteel, a fourth-year PhD candidate at ETSU, is following a similar high-achieving trajectory. Casteel was recently awarded the American Heart Association (AHA) Predoctoral Fellowship, a highly competitive and prestigious grant. The award provides $70,000 over two years, a significant milestone that marks him as one of the top emerging researchers in the field of cardiovascular health.

“It is a very good achievement for him,” Dr. Yakubenko said. “It is not just the money; it is also the self-esteem and the understanding that you can do it.”

By focusing on the tiny chemical reactions that make our tissues “sticky,” Dr. Yakubenko and his team are not just studying biology; they are mapping out a future where doctors can fine-tune the human immune system to save lives without the risk of a warrior’s friendly fire.