Mutations in rod photoreceptor-specific genes in retinitis pigmentosa (RP) cause diminished peripherial and night-time vision. But, it is secondary loss of cone function, leading to diminished high-resolution daylight vision utilized for reading, facial recognition and other daily tasks that is most debilitating. Events leading to loss of cone function in RP are still being unraveled. Like other neurons, photoreceptors depend upon glucose, which they use for energy as well as ongoing synthesis to replace visual pigment-rich membraneous outer segments (OS) as they undergo daily light-induced phagocytosis. The RPE serves as a blood-outer retinal barrier transporting glucose and nutrients from the choroid circulation to adjacent photoreceptors. We provide evidence that glucose transport from the RPE to photoreceptors for new OS synthesis is linked to OS phagocytosis. As abundant mutant rod OS are lost and phagocytosis diminishes in RP, glucose transport becomes short- circuited leading to cone starvation. We will examine the signaling pathway regulating glucose transport from the RPE and linked metabolome/epigenome changes in these cells during RP progression in both mice and pigs, a large animal model of RP where cones are concentrated into a visual streak.

Public Health Relevance

Although many mutations in retinitis pigmentosa (RP) arise in rod-specific genes, it is secondary loss of cone function, leading to diminished high-resolution daylight vision that is most debilitating. We provide evidence glucose transport from RPE to photoreceptors is diminished in RP, causing their starvation and loss of function. A pathway regulating glucose transport is identified, and we link its deregulation to RPE metabolome changes in RP.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY030933-01
Application #
9857356
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
2020-02-01
Project End
2025-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Louisville
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292