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Clinical and functional assessment of glaucoma-associated mitochondrial gene variants to facilitate precision eye care

Award Number: K23EY035734
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Clinical and functional assessment of glaucoma-associated mitochondrial gene variants to facilitate precision eye care - The NIH Precision Medicine Initiative was launched in 2015 with the goal of improving disease treatment and prevention based on understanding of genes, environment, and lifestyle. As a first step towards this goal, genome-wide association studies (GWAS), funded in part by the NIH, have identified 127 genes associated with risk for developing primary open-angle glaucoma (POAG) across multiple ancestries. However, this has not yet translated into personalized approaches for disease diagnosis, risk stratification, monitoring or treatment of this common, blinding disease. This proposal describes a 5-year training program for a clinician- scientist to develop a career focused on leveraging understanding of the genetic basis of glaucoma to optimize clinical care for afflicted individuals. I am well-suited to tackle this important unmet need. I have a strong research background in glaucoma genetics and continued this work under the mentorship of Dr. Janey Wiggs during my glaucoma fellowship at Mass. Eye and Ear. Our preliminary data demonstrate that POAG patients with high mitochondrial genetic risk scores have higher mean treated intraocular pressure (IOP) and markedly increased prevalence of paracentral field loss compared to patients with low mitochondrial genetic risk. These results suggest that POAG driven by mitochondrial risk variants may represent a distinct disease subtype with specific clinical features. However, the underlying molecular mechanism is unknown and deep clinical phenotyping is also warranted. In Aim 1, we will investigate the extent that individuals with high mitochondrial pathway-specific polygenic risk scores (PRSs) display elevated IOP, retinal mitochondrial dysfunction, distinct visual field loss patterns on archetypal analysis and greater susceptibility to environmental toxins that impact mitochondrial function. In Aim 2, we will characterize the functional impact of mitochondrial gene variants using disease-relevant primary cell strains (trabecular meshwork cells and retinal ganglion cells from human donor eyes) and ex vivo perfusions. The proposed work is geared to lay the groundwork for tailored approaches to disease monitoring and treatment for the subset of glaucoma driven by high mitochondrial genetic risk. Importantly, the research aims and proposed career development plan will provide me with new skills in statistical genetics and bioinformatics, clinical study design, deep clinical phenotyping, and functional assessment of conventional outflow cells and retinal ganglion cells. I will have access to all resources necessary to carry out the proposed work through Mass. Eye and Ear and the greater Harvard community. I am fortunate to have an outstanding team of mentors with expertise in glaucoma genetics (Drs. Janey Wiggs, Louis Pasquale, Ayellet Segre, and Jae Hee Kang), clinical data science (Dr. Tobias Elze), mitochondrial function (Dr. James Handa), conventional aqueous outflow pathobiology (Dr. Daniel Stamer) and retinal ganglion cell function (Dr. Donald Zack). Importantly, all members of my mentorship team are committed to my career development and facilitating my transition to an independent, R01-funded clinician-scientist investigator.


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: 2026 ( Subtotal = $269,782 )
2026	2026	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	3	12/4/2025	NON-COMPETING CONTINUATION	$269,782
														Subtotal = $269,782

Issue Date FY: 2025 ( Subtotal = $269,782 )
2025	2025	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	2	11/21/2024	NON-COMPETING CONTINUATION	$269,782
														Subtotal = $269,782

Issue Date FY: 2024 ( Subtotal = $269,782 )
2024	2024	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	1	11/30/2023	NEW	$269,782
														Subtotal = $269,782

Grand Total All Awards = $809,346

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Clinical and functional assessment of glaucoma-associated mitochondrial gene variants to facilitate precision eye care

Award Number: K23EY035734

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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