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Mechanisms of Angiogenesis in ROP

Award Number: R01EY015130
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/02/2004
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Mechanisms of Angiogenesis in ROP - PROJECT SUMMARY/ABSTRACT Agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) offer benefits over standard care laser treatment of the peripheral avascular retina in severe retinopathy of prematurity (ROP). Our lab provided proof of concept that regulating VEGF receptor 2 (VEGFR2) signaling in retinal endothelial cells (ECs) not only inhibited disordered intravitreal neovascularization (IVNV) in severe ROP, but also facilitated ordered EC division to allow vascularization into peripheral avascular retina (VPAR). VPAR occurs after intravitreal anti-VEGF treatment in infants with ROP, but reactivation with IVNV is difficult to distinguish from VPAR. To avoid complications from reactivated IVNV, clinicians tend to treat all new angiogenesis, but laser reduces potential VPAR and associated expanded visual field. Also, some anti-VEGFs reduce systemic VEGF levels with reports of adverse events in treated infants. There is the need to safely target pathologic VEGFR2 signaling to only inhibit IVNV and not VPAR. Our lab strives to understand signaling mechanisms that permit VPAR but inhibit IVNV in ROP without damaging the retina or the infant. We found that specifically in retinal ECs, regulation at the level of VEGF receptor 2 extended vascularization into the peripheral avascular retina, whereas endothelial STAT3 or the erythropoietin receptor (EPOR) either increased or inhibited IVNV. In our novel retinal EC culture model, we distinguished VEGF-activated tyrosine sites on the C-terminal domain (CTD) of VEGFR2. Sustained VEGFR2 signaling, important in p-ERK-mediated IVNV, activated the tyrosine (Y1175) site but not the Y1214. We also found that the adaptor proteins, MEMO1 and IQGAP1, sustained signaling through VEGFR2 leading to disordered or invasive angiogenesis in disease models. In transgenic humanized mice, signaling through the EPOR improved retinal function following oxygen induced damage. Based on our findings, we developed the hypothetical framework that regulation of angiogenesis leads to IVNV or VPAR and is mediated by signaling events involving1) activation of tyrosine phosphorylation sites on VEGFR2 or 2) adaptor proteins, e.g., MEMO1, IQGAP1, and that 3) crosstalk between EPOR and VEGFR2 signaling provides retinal vascular/neural protection. We propose 3 aims to test the prediction that: 1) IVNV will be increased by OIR- induced VEGF signaling through VEGFR2 in mice expressing mutant Y1212 (analog of human Y1214); 2) to test prediction that adaptor protein, MEMO1, interferes with Y1175 activation, whereas adaptor protein, IQGAP1, leads to Y1175 activation, retinal EC proliferation and IVNV; and 3) To test the prediction that crosstalk between VEGFR2 and EPOR signaling supports polarized retinal EC migration, as in VPAR, and that recovery of retinal neural function through EPOR involves EPOR-mediated vascular protection against high oxygen-induced damage. Methods include: novel mice with CRISPR-engineered mutations combined with conditional inducible knockout; optical coherence tomography; Micron IV imaging; OIR; OptoMotry and ERG.


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 = $378,303 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	23	7/17/2026	NON-COMPETING CONTINUATION	$378,303
														Subtotal = $378,303

Issue Date FY: 2025 ( Subtotal = $377,723 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	22	4/21/2025	NON-COMPETING CONTINUATION	$377,723
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	20	4/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,723

Issue Date FY: 2024 ( Subtotal = $377,723 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	21	8/12/2024	COMPETING CONTINUATION	$377,723
														Subtotal = $377,723

Issue Date FY: 2023 ( Subtotal = $388,372 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	004	20	9/1/2023	NON-COMPETING CONTINUATION	$388,373
2023	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	003	19	8/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$35,452
2023	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	18	4/7/2023	NON-COMPETING CONTINUATION	-$370,399
2023	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	19	4/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$370,398
2023	2021	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	002	17	8/30/2023	NON-COMPETING CONTINUATION	-$35,452
														Subtotal = $388,372

Issue Date FY: 2022 ( Subtotal = $370,399 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	18	9/8/2022	NON-COMPETING CONTINUATION	$370,399
														Subtotal = $370,399

Issue Date FY: 2021 ( Subtotal = $370,398 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	17	8/18/2021	NON-COMPETING CONTINUATION	$370,398
														Subtotal = $370,398

Issue Date FY: 2020 ( Subtotal = $513,409 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	001	16	8/21/2020	NON-COMPETING CONTINUATION	$381,854
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	002	16	9/2/2020	SUPPLEMENT FOR EXPANSION	$131,555
2020	2018	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	14	1/28/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $513,409

Issue Date FY: 2019 ( Subtotal = $394,978 )
2019	2019	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	15	8/6/2019	COMPETING CONTINUATION	$394,978
														Subtotal = $394,978

Issue Date FY: 2018 ( Subtotal = $373,026 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	14	8/13/2018	NON-COMPETING CONTINUATION	$373,026
														Subtotal = $373,026

Issue Date FY: 2017 ( Subtotal = $373,026 )
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	13	8/17/2017	NON-COMPETING CONTINUATION	$373,026
														Subtotal = $373,026

Issue Date FY: 2016 ( Subtotal = $373,026 )
2016	2016	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	12	8/18/2016	NON-COMPETING CONTINUATION	$373,026
														Subtotal = $373,026

Issue Date FY: 2015 ( Subtotal = $373,026 )
2015	2015	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	11	9/2/2015	NON-COMPETING CONTINUATION	$373,026
														Subtotal = $373,026

Issue Date FY: 2014 ( Subtotal = $381,608 )
2014	2014	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	001	10	8/15/2014	COMPETING CONTINUATION	$381,608
2014	2013	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	9	8/11/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $381,608

Issue Date FY: 2013 ( Subtotal = $342,045 )
2013	2013	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	9	6/25/2013	NON-COMPETING CONTINUATION	$342,045
														Subtotal = $342,045

Issue Date FY: 2012 ( Subtotal = $361,947 )
2012	2012	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	8	6/28/2012	NON-COMPETING CONTINUATION	$361,947
														Subtotal = $361,947

Issue Date FY: 2011 ( Subtotal = $361,857 )
2011	2011	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	7	6/23/2011	NON-COMPETING CONTINUATION	$361,857
														Subtotal = $361,857

Issue Date FY: 2010 ( Subtotal = $379,361 )
2010	2010	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Vision Research	000	6	7/2/2010	COMPETING CONTINUATION	$379,361
														Subtotal = $379,361

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2008	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Vision Research	000	4	6/25/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $277,870 )
2008	2008	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Vision Research	000	4	12/10/2007	NON-COMPETING CONTINUATION	$277,870
														Subtotal = $277,870

Issue Date FY: 2007 ( Subtotal = $283,541 )
2007	2007	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Vision Research	000	3	1/22/2007	NON-COMPETING CONTINUATION	$283,541
														Subtotal = $283,541

Issue Date FY: 2006 ( Subtotal = $281,634 )
2006	2006	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Vision Research	000	2	1/19/2006	NON-COMPETING CONTINUATION	$281,634
														Subtotal = $281,634

Grand Total All Awards = $7,615,612

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Mechanisms of Angiogenesis in ROP

Award Number: R01EY015130

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/02/2004

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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