Division of Biology and Biological Engineering

California Institute of Technology
Pasadena, CA

BASIC RESEARCH PROJECT

Targeting rhodopsin biogenesis and quality control in heritable retinal blindness

Research Interests

Retinitis Pigmentosa (RP) is a leading cause of genetically inherited blindness globally. RP impacts roughly 1 in 4,000 individuals worldwide, affecting approximately 1.5 million people. There are limited clinical interventions due to the sheer number of associated mutations and disease sub-types. Despite promising advances in stem cell and gene therapy, there are significant gaps in our understanding of the molecular basis of photoreceptor degeneration and disease progression. Rhodopsin mutations are commonly implicated in RP. Many of these mutants lead to accumulation of unfolded rhodopsin in the endoplasmic reticulum (ER) resulting in chronic activation of the unfolded protein response (UPR), which eventually triggers apoptosis and retinal atrophy. To develop effective therapies to delay or prevent retinitis pigmentosa-induced blindness, it is critical to understand the factors that regulate the UPR in photoreceptor cells. Understanding the molecular basis for RP pathogenesis and the resulting progressive vision loss is critical to developing much-needed treatments.

RP is commonly caused by mutations in the protein rhodopsin, which is a pigment that normally helps transform light into neuronal signals that are interpreted by the brain as sight. Rhodopsin is made in specialized cells within the retina called photoreceptors, which must first synthesize, fold, and transport rhodopsin to the thin waxy membrane that surrounds each cell. In RP, mutations in rhodopsin often lead to its mis-folding, so it cannot be shuttled to the cell surface and remains inappropriately trapped inside the cell.  Over time, the buildup of mis-folded rhodopsin triggers a cellular stress response pathway called the unfolded protein response. In the short term, this stress response is beneficial, because it globally slows protein production and simultaneously increases the levels of so-called ‘chaperones’ that can help fold rhodopsin. However, when cellular stress is chronically activated, this eventually leads to programmed cell death. Because the mutations in rhodopsin that lead to RP are genetically inherited, they trigger a constitutive stress response that results in loss of photoreceptor cells, leading to progressive and irreversible blindness. The factors that determine this delicate balance between the protective and destructive effects of the unfolded protein response are poorly understood, but are critical for understanding and intervening in Retinitis Pigmentosa.

Plans for 2026

Dr. Voorhees proposes to address this gap by leveraging her laboratory’s unique interdisciplinary platform for studying membrane protein biogenesis and quality control to identify factors required for the folding, transport, and degradation of rhodopsin. To do this, Dr. Voorhees will initially use her lab’s high-throughput genetic screening pipeline to find factors capable of attenuating the cell’s stress response during mutant rhodopsin production. The team will then characterize the molecular function of these factors to understand how they either interact with mutant rhodopsin and/or impact the signaling of cellular stress in the human retina. The goal of this work is to identify factors that contribute to dysregulation of stress in RP, and identify novel targets for therapeutics that can slow or prevent blindness.