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Role of Proteasome Overload in Pathogenesis of Retinitis Pigmentosa

Award Number: K08EY033857
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Role of Proteasome Overload in Pathogenesis of Retinitis Pigmentosa - PROJECT SUMMARY / ABSTRACT Retinitis pigmentosa (RP) is the most common hereditary cause of blindness, affecting over 1.5 million people worldwide. RP has an extraordinarily variable etiology, with over 5,000 distinct mutations in more than 300 genes implicated in its pathogenesis, which suggests that the most productive therapeutic interventions would employ gene-independent strategies to target the cellular pathology shared across many mutations and patient groups. Our lab has demonstrated that one such common pathology is the impairment of cellular proteostasis. This condition arises from the insufficient capacity of the ubiquitin-proteasome system to process large amounts of misfolded or mistargeted mutant proteins. Reducing this stress by enhancing ubiquitin- independent protein degradation causes a major delay in the degeneration of photoreceptors bearing the P23H rhodopsin mutation, a commonly encountered cause of human RP. We propose to expand the mechanistic investigation of proteostatic imbalance in mouse models of photoreceptor degeneration and plan to further explore practical approaches for restoration of proteostatic equilibrium. Our overarching goal is to identify optimal therapeutic strategies and drug targets that could be used to ameliorate these devastating blinding conditions. We will investigate whether enhancement of proteasomal activity achieved by directly targeting the 20S proteasome core can alleviate retinal degeneration in mouse RP models. Progression of photoreceptor degeneration in mouse models of RP can be considerably delayed by overexpressing the 11S regulatory cap, which facilitates the accessibility of protein substrates to the proteolytic sites located inside the 20S core. We propose to address whether a similar therapeutic effect could be achieved through direct manipulation of the 20S core by two complementary approaches – genetic and pharmacologic. The therapeutic effects of these strategies will be assessed in two mouse models of RP of dissimilar etiology – rhodopsin P23H mutation and the BBS4 knockout – and will include retinal histological analysis, electroretinography, and optomotor responses. The results of these experiments will demonstrate whether direct activation of 20S proteasomes can serve as a therapeutic strategy to treat inherited blindness. These data will encourage further investigations of proteasome activity enhancers and ultimately advancement to clinical trials for RP. Furthermore, promising results in RP models will encourage the evaluation of these drugs in models of other retinal degenerations and potentially neurodegenerative diseases, all of which exhibit proteostatic stress as a pathophysiological feature.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $170,704 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Vision Research	000	4	4/4/2025	NON-COMPETING CONTINUATION	$170,704
														Subtotal = $170,704

Issue Date FY: 2024 ( Subtotal = $170,704 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Vision Research	000	3	4/10/2024	NON-COMPETING CONTINUATION	$170,704
														Subtotal = $170,704

Issue Date FY: 2023 ( Subtotal = $170,704 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Vision Research	000	2	4/27/2023	NON-COMPETING CONTINUATION	$170,704
														Subtotal = $170,704

Issue Date FY: 2022 ( Subtotal = $170,704 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	1	4/13/2022	NEW	$170,704
														Subtotal = $170,704

Grand Total All Awards = $682,816

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Role of Proteasome Overload in Pathogenesis of Retinitis Pigmentosa

Award Number: K08EY033857

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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