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Laser speckle flowgraphy as early indicator of microvasculopathy in radiation-induced vision loss

Award Number: R01EY031544
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Laser speckle flowgraphy as early indicator of microvasculopathy in radiation-induced vision loss - PROJECT SUMMARY/ABSTRACT At least 50% of patients treated with 125I brachytherapy for uveal melanoma experience significant vision loss within 3-5 years after therapy. Extensive vascular pathology has been reported in the normal retina surrounding the melanoma after 2 years or more. These findings are in line with the accepted, but incompletely tested, concept that microangiopathy causes radiation-related vision loss due to injury of the microvascular endothelium during radiation. This leads to progressive capillary loss after a lag period of several years. If this hypothesis is correct, preventing the development of, or treating, radiation-induced endothelial damage in retinal microvessels will reduce capillary loss and save vision. However, this approach has been difficult to test because early indicators of microvascular endothelial dysfunction have yet to be established. The objectives of the proposed project are to: facilitate earlier detection, treatment and prevention of radiation- associated vision loss. Specifically, we expect to 1. detect early endothelial dysfunction based on reduced blood flow and response to light flicker 2. determine whether it is predictive of subsequent capillary loss and 3. identify molecular mechanisms of radiation-induced endothelial dysfunction. We will apply laser speckle flowgraphy (LSFG) for noninvasive, real-time imaging and measurement of ocular blood flow, in human subjects and mice to test our central hypothesis, that post-radiation endothelial dysfunction is driven by mitochondrial oxidative stress, and is predictive of the severity of subsequent capillary dropout and vision loss. We will test our hypothesis in two aims: Aim 1: Establish whether early impairment of the microvascular endothelial function will predict microvessel drop-out and vision loss in humans after 125I brachytherapy. For this purpose, LSFG, optical coherence tomography (OCT) and OCT-angiography (OCT-A) and tests of visual function will be performed in a prospective cohort of patients undergoing 125I brachytherapy for choroidal melanoma. We will test whether early impairment of ocular blood flow and flicker light-induced vasodilation by LSFG correlate with subsequent vision loss and capillary drop-out (as detected by OCT-A). Aim 2: Test whether selective inhibition of mitoROS production in endothelium prevents the early reduction of blood flow and subsequent loss of capillaries after radiation. In this aim, genetic mouse models in which key regulators of mitochondrial superoxide production are inhibited or overexpressed will be used to test whether inhibition of mitochondrial ROS in the endothelium protects from early impairment of retinal blood flow, endothelial dysfunction and subsequent capillary dropout. The expected outcomes of the proposed studies are knowledge of biomarkers of early radiation retinopathy and insights into the role of endothelial-cell mitochondrial dysfunction in radiation retinopathy. Our studies have the potential to facilitate the development of first-in-class, targeted therapies for radiation-related vision loss.


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 = -$316,351 )
2026	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	003	5	2/11/2026	NON-COMPETING CONTINUATION	$0
2026	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	002	6	1/23/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$316,351
2026	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	5	1/23/2026	NON-COMPETING CONTINUATION	-$316,351
2026	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	001	6	1/23/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$316,351
														Subtotal = -$316,351

Issue Date FY: 2024 ( Subtotal = $489,521 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	5	5/21/2024	NON-COMPETING CONTINUATION	$489,521
														Subtotal = $489,521

Issue Date FY: 2023 ( Subtotal = $489,521 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	4	5/9/2023	NON-COMPETING CONTINUATION	$489,521
														Subtotal = $489,521

Issue Date FY: 2022 ( Subtotal = $474,836 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	3	4/29/2022	NON-COMPETING CONTINUATION	$474,836
														Subtotal = $474,836

Issue Date FY: 2021 ( Subtotal = $861,043 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	1	4/16/2021	SUPPLEMENT FOR EXPANSION	$386,208
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	001	2	4/26/2021	NON-COMPETING CONTINUATION	$474,835
														Subtotal = $861,043

Issue Date FY: 2020 ( Subtotal = $489,521 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	1	5/7/2020	NEW	$489,521
														Subtotal = $489,521

Grand Total All Awards = $2,488,091

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Laser speckle flowgraphy as early indicator of microvasculopathy in radiation-induced vision loss

Award Number: R01EY031544

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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