Aim 1. Establish interventions for early disease in the transgenic rhodopsin P347L (TgP347L) rabbit, a model of human retinitis pigmentosa (RP). TgP347L (1-30 month old) rabbits (1-30 month old) will receive subretinal injections of shRNA-adeno-associated virus (AAV) to suppress mutant opsin production. Analyses include eye imaging, electroretinograms, visual evoked po- tentials, behavior, immunocytochemistry, Western blots, automated transmission electron micro- scope (ATEM) imaging, and electrophysiology by whole cell and multielectrode arrays. Signifi- cance. This is a test of early intervention for human RP in a large-eye animal model.
Aim 2. Establish optogenetic interventions for late disease in RP. TgP347L rabbits >12mos of age will receive (1) subretinal injections of Channelrhodopsin2 (ChR2)-AAV targeting bipolar cells (BCs) or AII amacrine cell (ACs). Analyses will follow those established in Aim 1. Signifi- cance. This is a test of late intervention for human RP in a large-eye animal model.
Aim 3. Build pathoconnectomes for early and late stage TgP347L rabbit BCs and AII cells. BCs are known to undergo severe rewiring and reprogramming in RP, but the nature of retargeting is completely unknown. The extent of AII cell remodeling is similarly unknown. Methods. ATEM imaging will be used to characterize remodeling networks. Significance. This is the first attempt to quantitatively define rewiring in any neural system in retina or brain and has profound implica- tions for all neurodegenerative disorders.
Aim 4. Evaluate retinoic acid and retinoid receptor-based interventions to attenuate corruptive remodeling and reprogramming. TgP347L rabbits will be treated with retinoid X receptor an- tagonists to block pathologic neuritogenesis. Analysis includes ATEM imaging and molecular profiling as in Aim 1. Significance. This is a test of a potential clinical intervention for remodel- ing RP in a large-eye animal model.
EY015128 New RNA inhibition and optogenetics interventions offer potential cures for retinitis pigmentosa (RP), even in the presence neuronal remodeling that impedes other therapies. Discovery of the mechanisms remodeling are facilitating anti-remodeling drug testing that may enhance the ef- fectiveness of gene therapies.
| Marc, Robert E; Sigulinsky, Crystal Lynn; Pfeiffer, Rebecca L et al. (2018) Heterocellular Coupling Between Amacrine Cells and Ganglion Cells. Front Neural Circuits 12:90 |
| Nagarajan, N; Jones, B W; West, P J et al. (2018) Corticostriatal circuit defects in Hoxb8 mutant mice. Mol Psychiatry 23:1-10 |
| Loizos, Kyle; Marc, Robert; Humayun, Mark et al. (2018) Increasing Electrical Stimulation Efficacy in Degenerated Retina: Stimulus Waveform Design in a Multiscale Computational Model. IEEE Trans Neural Syst Rehabil Eng 26:1111-1120 |
| Nagarajan, N; Jones, B W; West, P J et al. (2017) Corticostriatal circuit defects in Hoxb8 mutant mice. Mol Psychiatry : |
| Yoshioka, Nayuta; Zangerl, Barbara; Nivison-Smith, Lisa et al. (2017) Pattern Recognition Analysis of Age-Related Retinal Ganglion Cell Signatures in the Human Eye. Invest Ophthalmol Vis Sci 58:3086-3099 |
| Kerzner, E; Lex, A; Sigulinsky, C L et al. (2017) Graffinity: Visualizing Connectivity in Large Graphs. Comput Graph Forum 36:251-260 |
| Wahlin, Karl J; Maruotti, Julien A; Sripathi, Srinivasa R et al. (2017) Photoreceptor Outer Segment-like Structures in Long-Term 3D Retinas from Human Pluripotent Stem Cells. Sci Rep 7:766 |
| Foster, James W; Wahlin, Karl; Adams, Sheila M et al. (2017) Cornea organoids from human induced pluripotent stem cells. Sci Rep 7:41286 |
| Phu, Jack; Khuu, Sieu K; Nivison-Smith, Lisa et al. (2017) Pattern Recognition Analysis Reveals Unique Contrast Sensitivity Isocontours Using Static Perimetry Thresholds Across the Visual Field. Invest Ophthalmol Vis Sci 58:4863-4876 |
| Molnár, Tünde; Yarishkin, Oleg; Iuso, Anthony et al. (2016) Store-Operated Calcium Entry in Müller Glia Is Controlled by Synergistic Activation of TRPC and Orai Channels. J Neurosci 36:3184-98 |
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