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Modulating the DNA Damage Repair System in Traumatic Optic Neuropathy

Award Number: K08EY037381
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Modulating the DNA Damage Repair System in Traumatic Optic Neuropathy - PROJECT SUMMARY Traumatic optic neuropathy (TON) is a rare and devastating condition with no effective treatment, leading to irreversible vision loss. The long-term goal of this proposal is to develop novel therapeutic strategies to promote retinal ganglion cell (RGC) survival and axonal regeneration following optic nerve injury. This aligns with the NEI area of emphasis to understand the visual neuroscience underlying the relay of visual information from the retina to the brain. The objective of this proposal is to investigate the role of DNA damage response (DDR) pathways, specifically inhibition of checkpoint kinase 1 (Chk1), in enhancing RGC survival and promoting neuroprotection. The central hypothesis is that modulating Chk1 activity can prevent RGC apoptosis and promote survival after injury. The rationale underlying this proposal is that targeting DDR pathways will identify new molecular targets for therapeutic intervention in TON, providing potential treatments that can be applied to other optic neuropathies due to orbital disease, including compressive optic neuropathy and radiation-induced optic neuropathy. The central hypothesis will be tested by pursuing three specific aims: 1) determine whether Chk1 inhibition or a combination of Chk1/Chk2 inhibition in responsible for increased RGC survival in vitro; 2) characterize the function of Chk1 isoforms in RGCs and identify their molecular partners using immunoprecipitation-mass spectrometry (IP-MS); and 3) investigate the role of Chk1 in mouse models of traumatic optic neuropathy. These aims will be evaluated using an innovative approach that combines pharmacological screens, siRNA knockdown, and advanced molecular techniques in both cultured mouse RGCs and mouse models of optic nerve injury. The proposed research is significant because it has the potential to uncover novel mechanisms of RGC neuroprotection and identify new therapeutic targets for optic neuropathies. The expected outcome of this work is an improved understanding of how DDR modulation can enhance RGC survival and function following injury. These results will have an important and immediate impact because they will establish a new approach to treating optic neuropathies by targeting the DDR involved in RGC death and survival. The findings from this study will provide the foundation for an R01 grant focused on further preclinical testing and eventually translating these findings into clinical applications for patients with optic nerve injuries. To accomplish the experiments proposed in this grant, I will need to expand my current knowledge through dedicated course work and mentorship, which will be essential to my development as an independent clinician-scientist.


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 = $257,785 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	1	8/7/2025	NEW	$257,785
														Subtotal = $257,785

Grand Total All Awards = $257,785

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Modulating the DNA Damage Repair System in Traumatic Optic Neuropathy

Award Number: K08EY037381

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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