As construction noises echo through the halls, students, faculty and staff of the Hydrocephalus Research Center at the IU Indianapolis School of Science pack into an already crowded conference room. Bonnie Blazer-Yost, professor of biology and director of the center, is set to deliver her weekly update. As she scans the room, she's reminded of how dramatically her research has evolved.
Only a few years ago, before $11.7 million in funding from the Department of Defense changed everything, it was a much smaller team. Blazer-Yost, her colleague Teri Belecky-Adams, professor of biology and neuroscience, and a few students.
Now, she and Belecky-Adams oversee a hub of more than 30 people spanning across multiple disciplines, all with one common goal: Finding a drug treatment for hydrocephalus, a debilitating condition caused by the excessive buildup of cerebrospinal fluid in the brain's ventricles.
"We started basically from scratch," Blazer-Yost said. "Now we have postdocs, graduate students, undergraduates, new faculty members. Along the way, everybody's developed a camaraderie in the center. They work like crazy, and to see that passion is extremely rewarding."
Every 15 minutes, a patient diagnosed with hydrocephalus receives a shunt. This medical device is implanted directly into the brain to divert excessive cerebrospinal fluid to other parts of the body. The problem is, too often, shunts fail. For pediatric patients, 50% fail within two years, leading not only to a childhood filled with repeated brain procedures, but a lifetime tied to the necessity of being close to a medical center in case of shunt failure.
Due to this, there's an impetus among researchers to find a non-surgical solution. Blazer-Yost, Belecky-Adams and the Hydrocephalus Research Center are among those leading the charge. Multiple years into funding, the team has overseen several successful advancements in their research, including a large-scale animal model.
Although the team has made significant progress, developing a drug therapy has proven far more sophisticated than Blazer-Yost initially expected.
"We naively went in thinking it was just an overproduction of cerebrospinal fluid," she said. "No. There's neuroinflammation involved. There are pressure changes involved. All of these work together in a complex manner."
The group has found most success utilizing TRPV4 antagonists. TRPV4 is like a tiny sensor on the surface of many cells that responds to things like pressure, stretching, temperature and certain chemicals. A TRPV4 antagonist turns down or blocks this sensor when it's overactive, which may help prevent excess fluid production, inflammation, pain or damage in some diseases. Most importantly, in limited clinical trials for other diseases, it's shown to have no adverse effects on humans.
As it pertains to hydrocephalus, TRPV4 antagonists, through models developed at the Hydrocephalus Research Center, have shown the ability to reduce cerebrospinal fluid production, the root of many problems associated with the disease. Additionally, it's proven useful in reducing the effects of neuroinflammation.
"What we've shown in tissue culture is that it decreases the production of cerebrospinal fluid," Blazer-Yost said. "That we're more sure about than neuroinflammation. We weren't originally expecting it to affect neuroinflammation, but it's possible it's a secondary consequence of expanding ventricles, so maybe if the ventricles don't expand, then you don't have neuroinflammation. It's also plausible TRPV4 does directly affect neuroinflammation."
To answer this, one Hydrocephalus Research Center model focuses on replicating the inflammatory response following a hemorrhage by introducing a small amount of blood. The amount is carefully controlled to trigger neuroinflammation without causing hydrocephalus, allowing researchers to determine whether neuroinflammation can occur independently of hydrocephalus and, if so, evaluate how TRPV4 affects that inflammation.
In fact, a goal driving the center is the prospect of developing a model for each of the various types of hydrocephalus, including post-infectious, the most prevalent pediatric form; normal pressure, most common in the elderly; post-hemorrhagic, occurring most often in premature infants and adults following stroke; and post-traumatic, caused by traumatic brain injuries.
"If we're able to develop relevant models for all types of hydrocephalus, it will make us very unique," Blazer-Yost said. "As drug compounds become available for testing, we can determine if they will be applicable for multiple forms of the disease. We can do it all right here at IU Indianapolis."
The team's latest research will be presented at the Hydrocephalus Association's HA Connect conference, July 23-25 in Indianapolis, where faculty and students will unveil some of their models, share findings with leading researchers from around the world and host tours of the center.
For Blazer-Yost, the upcoming conference represents more than an opportunity for students to showcase their research. It reflects how far the center has come, and how much closer it may be to expanding treatment options for patients living with hydrocephalus.
