Tuesday, July 1, 2025 7/1/2025

Endothelial Transmigration in Neovascular Age-related Macular Degeneration

Award Number: R01EY017011
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2007
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Endothelial Transmigration in Neovascular Age-related Macular Degeneration - Anti-VEGF therapies, standard care in neovascular age-related macular degeneration (nvAMD), improve outcomes in less than 50% of patients and do not prevent vision-loss progression due to fibrosis or macular atrophy. We used human physiologically relevant models to gain understanding into the coordination of signaling pathways and cross-talk involved in the activation of choroidal endothelial cells (CECs) to migrate and form macular neovascularization in nvAMD. The scaffolding protein, IQGAP1, sustains activation of the GTPase Rac1, which is necessary for CEC migration. Rac1 is activated by AMD-related stresses involving inflammatory, oxidative and angiogenic factors, as well as by the oxysterol, 7-ketocholesterol (7KC), which accumulates in blood and Bruch’s membrane with increased age and in AMD. 7KC causes CECs to change expression of cell markers from endothelial to mesenchymal ones, suggesting endothelial-mesenchymal transition (EndMT). IQGAP1 appears involved. 7KC also causes fibrosis in models of laser induced injury. Our data support the hypothetical framework that will be tested in the next funding period: that (1) IQGAP1 is critical to EndMT induced by the oxysterol 7KC; and that (2) 7KC triggers transcriptional events that render CECs unable to maintain expression of endothelial markers but to develop into a new phenotype of migratory, mesenchymal cells that develop into fibrosis. We will also test two potential therapies to reduce fibrosis: (a) to inhibit TGFβ signaling in combination with anti-VEGF and (b) to target phosphorylation of IQGAP1 in a novel mutant IQGAP1 mouse that we created by CRISPR-Cas9-induced gene mutation. Specific Aim 1 is to test the prediction that IQGAP1 mediates EndMT-induced migration in CECs exposed to 7KC. Specific Aim 2 is to test the prediction that 7KC, mediated through IQGAP1, decreases the proportion of labeled endothelial positive to mesenchymal positive cells after laser in endothelial specific yellow-fluorescent protein reporter mice. Specific Aim 3 is to test predictions that increased age, TGFβ-signaling, or IQGAP1 serine phosphorylation will increase αSMA-labeled lesions after laser in 7KC-treated eyes and to test strategies as possible future treatments. We will also evaluate the involvement of Müller cells, pericyes, and RPE. Tools include isolated human CECs; high throughput RNA sequencing; flow cytometry; spectral domain optical coherence tomography (sdOCT); 7KC-induced models of EndMT and fibrosis; yellow-fluorescent protein endothelial reporter mice; conditional inducible endothelial Iqgap1 knockout mice; a mutant IQGAP1 mouse through CRISPR-Cas9-technology; intravitreal injections of pharmacologic agents; Micron IV laser induced injury to test 7KC-induced EndMT and lesion formation. These studies will test the role of IQGAP1 in 7KC-induced EndMT as a potential cause of fibrosis, which is poorly responsive to anti-VEGF in nvAMD, and will test two novel treatments to reduce nvAMD and EndMT.


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 = $451,009 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	20	4/2/2025	NON-COMPETING CONTINUATION	$451,009
														Subtotal = $451,009

Issue Date FY: 2024 ( Subtotal = $515,692 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	002	19	3/13/2024	NON-COMPETING CONTINUATION	$515,692
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	18	1/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$369,117
2024	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	17	1/11/2024	COMPETING CONTINUATION	-$369,117
														Subtotal = $515,692

Issue Date FY: 2023 ( Subtotal = $509,777 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	18	4/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$509,777
2023	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	17	4/6/2023	COMPETING CONTINUATION	$0
														Subtotal = $509,777

Issue Date FY: 2022 ( Subtotal = $437,325 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	001	17	4/19/2022	COMPETING CONTINUATION	$437,325
2022	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	002	16	8/25/2022	NON-COMPETING CONTINUATION	$0
2022	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	16	4/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $437,325

Issue Date FY: 2021 ( Subtotal = $369,812 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	16	3/24/2021	NON-COMPETING CONTINUATION	$369,812
														Subtotal = $369,812

Issue Date FY: 2020 ( Subtotal = $381,250 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	15	3/20/2020	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2019 ( Subtotal = $381,250 )
2019	2019	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	14	2/14/2019	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2018 ( Subtotal = $380,625 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	001	13	5/11/2018	NON-COMPETING CONTINUATION	$38,063
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	13	3/21/2018	NON-COMPETING CONTINUATION	$342,562
														Subtotal = $380,625

Issue Date FY: 2017 ( Subtotal = $444,454 )
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	003	12	8/21/2017	COMPETING CONTINUATION	$31,227
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	001	12	7/24/2017	SUPPLEMENT FOR EXPANSION	$66,016
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	12	1/11/2017	COMPETING CONTINUATION	$378,438
2017	2016	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	002	11	8/21/2017	EXTENSION WITH OR WITHOUT FUNDS	-$31,227
														Subtotal = $444,454

Issue Date FY: 2016 ( Subtotal = $372,500 )
2016	2016	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	11	3/21/2016	EXTENSION WITH OR WITHOUT FUNDS	$372,500
														Subtotal = $372,500

Issue Date FY: 2015 ( Subtotal = $451,021 )
2015	2015	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	001	10	9/2/2015	SUPPLEMENT FOR EXPANSION	$85,971
2015	2015	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	10	3/18/2015	NON-COMPETING CONTINUATION	$365,050
														Subtotal = $451,021

Issue Date FY: 2014 ( Subtotal = $365,050 )
2014	2014	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	9	3/21/2014	NON-COMPETING CONTINUATION	$365,050
														Subtotal = $365,050

Issue Date FY: 2013 ( Subtotal = $354,171 )
2013	2013	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	001	8	6/13/2013	NON-COMPETING CONTINUATION	$18,640
2013	2013	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	8	4/24/2013	NON-COMPETING CONTINUATION	$335,531
														Subtotal = $354,171

Issue Date FY: 2012 ( Subtotal = $373,750 )
2012	2012	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	001	7	3/30/2012	COMPETING CONTINUATION	$373,750
2012	2011	UNIVERSITY OF UTAH, COLLEGE OF MEDICINE	50 NORTH MEDICAL DRIVE	SALT LAKE CITY	UT	84102	SALT LAKE	USA	Vision Research	000	6	3/28/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $373,750

Issue Date FY: 2011 ( Subtotal = $284,669 )
2011	2011	UNIVERSITY OF UTAH, COLLEGE OF MEDICINE	50 NORTH MEDICAL DRIVE	SALT LAKE CITY	UT	84102	SALT LAKE	USA	Vision Research	000	6	2/18/2011	NON-COMPETING CONTINUATION	$266,877
2011	2011	UNIVERSITY OF UTAH, COLLEGE OF MEDICINE	50 NORTH MEDICAL DRIVE	SALT LAKE CITY	UT	84102	SALT LAKE	USA	Vision Research	001	6	6/22/2011	NON-COMPETING CONTINUATION	$17,792
														Subtotal = $284,669

Issue Date FY: 2010 ( Subtotal = $287,714 )
2010	2010	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Vision Research	001	4	7/30/2010	NON-COMPETING CONTINUATION	-$191,809
2010	2010	UNIVERSITY OF UTAH, COLLEGE OF MEDICINE	50 NORTH MEDICAL DRIVE	SALT LAKE CITY	UT	84102	SALT LAKE	USA	Vision Research	002	5	8/3/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$191,809
2010	2010	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Vision Research	000	4	2/24/2010	NON-COMPETING CONTINUATION	$287,714
														Subtotal = $287,714

Issue Date FY: 2009 ( Subtotal = $739,488 ) (Continued on the next page)
2009	2009	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Vision Research	000	3	2/23/2009	NON-COMPETING CONTINUATION	$261,558
2009	2009	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Vision Research	002	3	9/11/2009	SUPPLEMENT FOR EXPANSION	$448,868
Grand Total All Awards = $7,731,885

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Endothelial Transmigration in Neovascular Age-related Macular Degeneration

Award Number: R01EY017011

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2007

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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