The long-term goal of this research program is to understand the molecular and cellular mechanisms underlying retinal degeneration and to seek potential therapeutic approaches alleviating or slowing disease progression. In this application, we propose to explore the hypothesis that a major stress factor contributing to photoreceptor cell death in retinitis pigmentosa and related diseases is insufficient ability of proteasomes to degrade large amounts of misfolded or mistargeted proteins that appear as a result of the underlying pathology. Our preliminary data indicate that proteasomal insufficiency is observed at early stages of photoreceptor degeneration in four different mouse models and, in some cases, this impairment becomes prominent before the earliest morphological abnormalities could be identified.
Aim 1 will be devoted to a detailed mechanistic characterization of proteasomal insufficiency in degenerating rods of two complementary animal models, transducin ?-subunit knockout and P23H mouse. Most importantly, we will address whether affected photoreceptors suffer from proteasomal overload, i.e. insufficient capacity of their proteasomes to process abnormally high loads of misfolded proteins, or the underlying pathology affects proteasomes directly by inhibiting their activity or altering their subunit composition.
Aim 2 will explore the prevalence of proteasomal insufficiency across different forms of retinal degeneration. We will test whether it could be detected in rods suffering from aberrant signaling in the phototransduction cascade and elucidate whether it takes place in mice suffering from mutations which affect cones more significantly than rods.
Aim 3 will evaluate whether proteasomes could serve as a therapeutic target in treating retinal degenerative diseases. We will explore whether the onset of pathology can be slowed or prevented by gene therapy or pharmacological treatments designed to increase proteasomal activity in affected photoreceptors.
Inherited degenerative diseases of the retina, including retinitis pigmentosa, affect approximately one in 2000 individuals worldwide and represent a genetically and phenotypically heterogeneous group of visual disorders characterized by progressive photoreceptor cell death. Currently, there is no effective treatment to prevent or significantly slow this disease. The studies proposed in this application provide new critical insights into our understanding of the molecular nature of cellular stressors which trigger the progression of these pathological conditions. We will also explore several experimental strategies designed to alleviate this underlying cellular stress, including gene therapy and pharmaceutical interventions. The therapeutic interventions based on these strategies have a strong potential to stop or slow the progression of retinal degenerations, thereby preventing visual loss in patients suffering from these debilitating conditions.
| Dexter, Paige M; Lobanova, Ekaterina S; Finkelstein, Stella et al. (2018) Transducin ?-Subunit Can Interact with Multiple G-Protein ?-Subunits to Enable Light Detection by Rod Photoreceptors. eNeuro 5: |
| Sharif, Ali S; Yu, Dongmei; Loertscher, Stuart et al. (2018) C8ORF37 Is Required for Photoreceptor Outer Segment Disc Morphogenesis by Maintaining Outer Segment Membrane Protein Homeostasis. J Neurosci 38:3160-3176 |
| Lobanova, Ekaterina S; Finkelstein, Stella; Li, Jing et al. (2018) Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration. Nat Commun 9:1738 |
| Kim, Sanghoon; Heflin, Stephanie; Kresty, Laura A et al. (2016) Analyzing spatial correlations in tissue using angle-resolved low coherence interferometry measurements guided by co-located optical coherence tomography. Biomed Opt Express 7:1400-14 |
| Arshavsky, Vadim Y; Burns, Marie E (2014) Current understanding of signal amplification in phototransduction. Cell Logist 4:e29390 |
