William Spencer, PhD, of Upstate Medical University has received a five-year, $2.3 million R01 grant from the National Eye Institute (NEI), part of the National Institutes of Health, to investigate how the retina’s light-sensing structures are built and maintained. Better understanding this process could help develop treatments for currently incurable retinal diseases that lead to blindness. Spencer is an assistant professor of ophthalmology & visual sciences and a member of Upstate's Center for Vision Research (CVR).
The project focuses on the photoreceptor outer segment, the light-sensitive antenna of photoreceptor cells that is constantly renewed throughout a person’s life. Each day, dozens of new disc-shaped membranes containing photopigment are added to the outer segment while old ones are discarded. Mutations in the proteins that support the ongoing formation of these membranes can lead to inherited retinal degenerative diseases, including retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis, which in most cases end in complete blindness.
"This project addresses a long-standing mystery about our vision: how outer segments are built and maintained at the molecular level," says Spencer. "At present, there is a complete lack of therapies for retinal diseases caused by defects in outer segment formation. A major barrier to developing treatments is that we don't fully understand how the light-sensing structures are built. How could we fix something that we don't understand in the first place?"
The research centers on two genes, PRCD and KIAA1549, both linked to retinitis pigmentosa in humans. Spencer's previous work shows that the proteins they produce play a role in the first steps of building the light-sensitive membrane material packed inside outer segments.
"Like intricate origami, these light-sensitive membranes must be folded into perfectly flat membrane layers, an arrangement that maximizes the efficiency of light capture," Spencer explains. "Without PRCD or KIAA1549, these membranes are folded and packed in a highly disorganized fashion, which leads to cell dysfunction, cell death, and blindness."
The grant supports two research aims. The first explores the molecular mechanism underlying PRCD’s ability to keep the outer segment’s membrane layers tightly adhered together in the first steps of their morphogenesis. The second aim explores how KIAA1549 regulates disc formation via a structure called the connecting cilium, which is a tubular conduit that physically links the outer segment to the photoreceptor cell body.
"We aim to unravel the molecular mechanisms underlying the function of PRCD and KIAA1549 in photoreceptor cells and hope this will lead to the development of novel therapies for blinding retinal disease."
You can find more information about Spencer’s research at SpencerVisionLab.org .
Want to learn more about vision research happening at Upstate? Visit the Center for Vision Research’s website at https://www.upstate.edu/cvr .