The severe loss of photoreceptor cells in retinal degenerative diseases could result in partial or complete blindness. Currently, once the photoreceptors are lost, there is no effective treatment available for restoring lost vision. We are exploring a novel strategy of genetically converting light-insensitive second- or third-order retinal neurons into photosensitive cells, thus imparting light-sensitivity to retinas that lack photoreceptors. Proof-of-concept studies have demonstrated the feasibility of the functional expression of channelrhodopsin-2 (ChR2) and halorhodopsin (HaloR) in inner retinal neurons and resulting restoration of ON and OFF light responses in the retina of a mouse model with retinal degeneration. The objective of this proposal will continue the proof-of-principle studies in rodent models to address issues that are important for developing this treatment strategy for clinical applications. Specifically, we will study the long-term expression of HaloR in inner retinal neurons in vivo and investigate the underlying mechanism(s) of ChR2 and HaloR-mediated light responses in retinal neurons. We will also explore targeted expression of ChR2 and HaloR to specific population(s) of inner retinal neurons and/or sub cellular compartments of retinal ganglion cells. Furthermore, we will investigate the ChR2 and HaloR-mediated light response properties from the targeted cells and their downstream neurons in normal and retinal degenerative mice. Our long-term goal is to develop a novel strategy for treating or curing blindness caused by retinal degeneration. The proposed studies will provide critical knowledge in animal models required for advancing this new treatment strategy to clinical applications. The studies will also advance our knowledge of retinal circuitry and functions under normal and diseased conditions as well as develop new tools for basic retinal research.
Our goal is to develop a novel strategy for treating or curing blindness caused by retinal degeneration. If successful, this strategy could be potentially used to treat or cure all common blindness caused by photoreceptor loss.
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|Zhang, Zhifei; Feng, Jie; Wu, Chaowen et al. (2015) Targeted Expression of Channelrhodopsin-2 to the Axon Initial Segment Alters the Temporal Firing Properties of Retinal Ganglion Cells. PLoS One 10:e0142052|
|Lu, Qi; Ivanova, Elena; Ganjawala, Tushar H et al. (2013) Cre-mediated recombination efficiency and transgene expression patterns of three retinal bipolar cell-expressing Cre transgenic mouse lines. Mol Vis 19:1310-20|
|Ivanova, Elena; Lee, Patrick; Pan, Zhuo-Hua (2013) Characterization of multiple bistratified retinal ganglion cells in a purkinje cell protein 2-Cre transgenic mouse line. J Comp Neurol 521:2165-80|
|Wu, Chaowen; Ivanova, Elena; Zhang, Yi et al. (2013) rAAV-mediated subcellular targeting of optogenetic tools in retinal ganglion cells in vivo. PLoS One 8:e66332|
|Cui, J; Ivanova, E; Qi, L et al. (2012) Expression of CaV3.2 T-type Caýýýýý channels in a subpopulation of retinal type-3 cone bipolar cells. Neuroscience 224:63-9|
|Wu, Chaowen; Ivanova, Elena; Cui, Jinjuan et al. (2011) Action potential generation at an axon initial segment-like process in the axonless retinal AII amacrine cell. J Neurosci 31:14654-9|
|Ivanova, Elena; Hwang, Grace-Soon; Pan, Zhuo-Hua et al. (2010) Evaluation of AAV-mediated expression of Chop2-GFP in the marmoset retina. Invest Ophthalmol Vis Sci 51:5288-96|
|Ivanova, Elena; Roberts, Robin; Bissig, David et al. (2010) Retinal channelrhodopsin-2-mediated activity in vivo evaluated with manganese-enhanced magnetic resonance imaging. Mol Vis 16:1059-67|
|Ivanova, E; Hwang, G-S; Pan, Z-H (2010) Characterization of transgenic mouse lines expressing Cre recombinase in the retina. Neuroscience 165:233-43|
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