Area:
retinal degeneration, rhodopsin folding and signaling
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High-probability grants
According to our matching algorithm, Yuanyuan Chen is the likely recipient of the following grants.
| Years |
Recipients |
Code |
Title / Keywords |
Matching
score |
| 2020 — 2021 |
Chen, Yuanyuan |
R01Activity Code Description:
To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pharmacological Studies of Rhodopsin Metabolism @ University of Pittsburgh At Pittsburgh
Summary: Genetic mutations of the dim-light visual pigment, rhodopsin (Rho), cause retinitis pigmentosa (RP), and no effective pharmacological treatment is available for this inherited retinal degeneration. Our long-term goal is to determine the molecular events that contribute to photoreceptor death in RP and develop effective small molecule drugs targeting these events that preserve the retinal structure and visual function. Rho protein misfolding causes rod cell death in RP. Our central hypothesis is: small molecules that stabilize Rho structure, or those induce degradation of misfolded Rho can mitigate Rho-associated adRP. We recently discovered two novel and potent lead compounds: 1) YC-001, a non-retinal chaperone of Rho that rescues folding of multiple misfolded Rho mutants that cause RP; and 2) a U.S. Food and Drug Administration (FDA)-approved drug that induces misfolded Rho degradation in vitro, and that possesses potent anti-inflammatory activity. Using the well-studied Rho P23H knock-in mouse model of RP, we will determine the efficacy, mechanism of action, and safety of these two compounds firstly in the isolated retinae explant culture, and then in vivo by an intravitreal injection of YC-001 encapsulated in a controlled drug release formula, or via intermittent intravitreal injections of the FDA-approved drug with optimized intervals. We will utilize state-of-the-art retinal imaging and electrophysiology techniques to evaluate the retinal structure and visual function. We will conduct biochemical and transcriptome analyses to identify the drug targeting pathways that regulate rhodopsin homeostasis. The results from this study will provide comprehensive pharmacological profiles of the two lead compounds in a rodent model of adRP, from which we will build a clear molecular network connecting rhodopsin expression, folding, degradation and retinal inflammation with the progression of retinal degeneration and we will assess the efficacy of these compounds as potential treatments for RP.
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