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Chen Lab - Research Opportunities

Development of Novel Therapies for Dominant CRX Disease

Background: Mutations of the transcription factor CRX are associated with dominant forms of Retinitis Pigmentosa, Cone-Rod Dystrophy and Leber’s Congenital Amaurosis. Using a Knock-IN strategy, we introduced E168d2, an equivalent human disease causing mutation into the mouse Crx gene. The Crx E168d2 Knock-IN mouse exhibits delayed photoreceptor development, impaired retinal function and slow cone degeneration with a pathology similar to the human disease. The E168d2 model will allow us to investigate the mechanisms of dominant disease as well as develop novel therapies.

Rotation project: Due to the progressive disease pathology, prevention of retinal degeneration is a critical therapeutic strategy. In addition to slow cone degeneration, E168d2 photoreceptors are much more susceptible than wild-type mice to Light-Induced toxicity. Light-induced toxicity results from acute metabolic, ER, and oxidative stress in the photoreceptors, implicating these pathways in disease progression and severity. The goal of this project would be to target stress pathways using small molecule drugs that are neuroprotective, anti-oxidant and epigenetic regulators (such as histone deacetylase inhibitors HDACi) and evaluate their potential to prevent light-induced photoreceptor degeneration in the E168d2 mouse model. This will serve as a pilot project with direct clinical relevance for developing novel therapeutic strategies for CRX-associated diseases.

Dr. Shiming Chen: 
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