Researchers awarded $2.7 million NIH grant to study retinal connections in RP
USC is leading a research team aiming to better understand retinitis pigmentosa and inform future treatments.
(Image credit: AdobeStock/Prostock-studio)
A collaborative team from the University of Southern California (USC) and the University of Utah has secured a $2.7 million grant from the National Institutes of Health (NIH) to investigate how retinitis pigmentosa (RP), an incurable eye disease, disrupts the visual wiring in the retina. The study aims to uncover insights that could lead to strategies for slowing or preventing vision loss.
According to a USC news release, retinitis pigmentosa is a progressive condition marked by four distinct stages that gradually affect the retina, the light-sensitive tissue at the back of the eye responsible for converting light into electrical signals for the brain. The research team plans to create detailed maps of the retina's nerve connections at each stage of RP, tracking how these networks deteriorate over time.1
An inherited disease impacting approximately 2 million people worldwide, RP typically begins in childhood and causes retinal cells to degenerate. The condition progressively leads to peripheral vision loss, gradually narrowing the field of sight until blindness occurs.
“We’re optimistic that this is the right time for this project,” said principal investigator Gianluca Lazzi, PhD, a USC Provost Professor of Ophthalmology at the Keck Scholl of Medicine of USC and of Electrical and Computer Engineering, Clinical Entrepreneurship, and Biomedical Engineering at the USC Viterbi School of Engineering. “We know how to handle data in a way that was unimaginable even 5 years ago. We believe this will keep growing while we’re doing the work, enabling us to handle even more.”
The retina’s nerve network, known as a "connectome," serves as a detailed wiring diagram that illustrates how neurons transmit signals. By correlating structural changes in the retina with functional disruptions, the researchers aim to uncover critical insights that could inform new strategies to combat retinitis pigmentosa.
“There’s an old saying, ‘Don’t tell me what it is; tell me what it does,’” said Lazzi, who is also the Fred H. Cole Professor of Engineering at USC Viterbi. “We want to bring the entire network to life with functional models — showing what the disease does — that can be used by everybody working in this field. Collectively, we’ll have a better shot at developing effective therapies.”
In retinitis pigmentosa, the death of retinal cells triggers a cascade of secondary issues that are a key focus for Lazzi and his team. When retinal cells die, they leave healthy neurons without connections. These neurons then form improper links with the wrong cells, disrupting normal signaling and exacerbating the damage.1
Lazzi, also director of the USC Institute for Technology and Medical Systems, noted that one neuron dies, and the other realizes no one is receiving the signal, but talking to somebody else turns out to be a bad idea.
“If we can unlock what drives this change, we can imagine a future where we can drive the neuron to make a better connection, one that slows progression of the disease,” he explained.
The team, which unites USC Viterbi, the Keck School of Medicine of USC, the USC Dornsife College of Letters, Arts and Sciences and the University of Utah School of Medicine, uses two complementary imaging techniques for the connectome: two-photon excitation microscopy and transmission electron microscopy.
Michael Bienkowski, PhD, an assistant professor of physiology and neuroscience at USC, is leading efforts to visualize the entire retinal system using two-photon excitation microscopy. This advanced imaging technique enables researchers to peer deep into tissue without causing damage, tagging distinct populations of neurons with fluorescent colors for detailed analysis. As the director of the USC Center for Integrative Connectomics and a member of the USC Laboratory of Neuro Imaging at the USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Bienkowski has developed an innovative method to selectively label neurons by using a modified, non-infectious form of the rabies virus to deliver fluorescent dye.
“Mike’s technique allows us to image a precise layer of the retina,” Lazzi said. “We can capture the entire image of, say, all the ganglion cells, so there’s no confusion between different types of neurons. This is a huge advantage.”
The team is also utilizing transmission electron microscopy, a powerful imaging technique that captures details smaller than the wavelength of light, allowing scientists to closely examine individual synapses where neurons connect. This aspect of the research is led by retinal neuroscientist Bryan Jones, PhD, of the University of Utah, who also oversees the specialized laboratory models essential for the study.1
Lazzi focuses on computational analysis and modeling, supported by Jean-Marie Bouteiller, PhD, a USC research associate professor of biomedical engineering. Their work incorporates artificial intelligence to identify key features of healthy neurons. Meanwhile, electrophysiologist Steven Walston, PhD, an assistant professor of research ophthalmology at the Keck School of Medicine, is tasked with validating the team’s findings by analyzing electrical signaling in the retina.
“Steve’s contributions enable us to correlate the results of the computational models with experimental measurements,” said Lazzi. “Right now we don’t have a very clear answer to how a given cell in stage four of degeneration responds to stimuli. We’re looking for those answers.”
This grant builds on prior research supported by the NIH and the National Science Foundation, which included electron microscopy-based models of retinal connections in both healthy conditions and the early stages of retinitis pigmentosa. Lazzi characterizes the team’s work as convergent research—a mission-driven collaboration that integrates expertise from diverse fields at every stage of the project.
Lazzi said the project is true cross-fertilization.
“We’re working together on an entire mesh of activities. In that environment, you learn and adapt,” he concluded. “You operate in areas that might push the borders of the box you’re used to. But that’s entirely the point — there shouldn’t be a box, right?”
