NIH grant funds cell research on inherited retinal disease mechanisms

William Spencer, PhD, an assistant professor of ophthalmology and visual sciences at State University of New York Upstate Medical University, has received a five-year, $2.3 million R01 grant from the National Eye Institute, part of the National Institutes of Health, to investigate how photoreceptor outer segments are built and maintained. The cell-biology research focuses on two genes, PRCD and KIAA1549, whose proteins help support the formation of light-sensitive membrane discs in photoreceptors. Mutations affecting proteins involved in this process can cause inherited retinal degenerative diseases, including retinitis pigmentosa, cone-rod dystrophy and Leber congenital amaurosis, which in most cases end in complete blindness. The grant supports research into the underlying molecular mechanisms; it does not establish a treatment or report clinical outcomes.

Photoreceptor outer segments are described as the light-sensitive antennae of photoreceptor cells. They are continuously renewed throughout a person’s life: each day, photoreceptors add dozens of new disc-shaped membranes containing photopigment to the outer segment while discarding old ones. These membranes must be folded into flat layers and packed precisely, a process Spencer compared to intricate origami. The arrangement maximizes the efficiency of light capture. Earlier work from Spencer’s laboratory found that the proteins produced by PRCD and KIAA1549 participate in the first steps of constructing the membrane material packed inside outer segments. Without these proteins, the membranes are folded and packed in a highly disorganized fashion, leading to cell dysfunction, cell death and blindness.

The five-year award has two specific aims. The first will examine the molecular mechanism through which PRCD keeps the outer segment’s membrane layers tightly adhered during the earliest stages of their morphogenesis. The second will examine how KIAA1549 regulates disc formation through the connecting cilium, a tubular conduit that physically links the outer segment to the photoreceptor cell body. Together, the aims address two molecular processes associated with outer-segment formation: membrane assembly and the cellular structure involved in disc formation. Spencer said the project seeks to unravel the molecular mechanisms underlying the function of PRCD and KIAA1549 in photoreceptor cells, with the stated hope that the work could contribute to the development of novel therapies for blinding retinal disease.

Spencer described the project as addressing a long-standing molecular mystery about vision: how outer segments are built and maintained. He said there is a complete lack of therapies for retinal diseases caused by defects in outer-segment formation and that a major barrier to developing treatments is an incomplete understanding of how the light-sensing structures are built. The R01 award therefore funds mechanistic investigation into a knowledge gap associated with inherited retinal disease. The announcement identifies no drug candidate, clinical trial or immediate therapeutic application resulting from the grant. Instead, its stated purpose is to define how the two genes’ proteins operate in photoreceptors, with potential therapeutic development presented as a hoped-for consequence of that work rather than an established outcome.

Subject of Research: Molecular mechanisms of photoreceptor outer-segment formation in inherited retinal disease

Article Title: Upstate researcher receives $2.3 million grant to study causes of blindness

Article References: Upstate researcher receives $2.3 million grant to study causes of blindness. Original publication (Bibliographic details unavailable.)

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Keywords: photoreceptor outer segments, PRCD gene, KIAA1549 gene, retinitis pigmentosa, retinal degeneration, photoreceptor renewal, National Eye Institute, inherited blindness, cell biology, Upstate, researcher, receives