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The role of the Wnt signaling pathway in choroidal neovascularization

Award Number: R01EY018659
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2021

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The role of the Wnt signaling pathway in choroidal neovascularization - ¿ DESCRIPTION (provided by applicant): Choroidal neovascularization (CNV) in AMD is a leading cause of vision loss. Oxidative stress and inflammation in the retina and RPE are believed to play important pathogenic roles in CNV. The canonical Wnt pathway is known to mediate inflammation, angiogenesis and fibrosis. Our previous studies have shown that very low-density lipoprotein receptor (VLDLR) knockout (KO) results in Wnt pathway over-activation, retinal inflammation and sub-retinal neovascularization (NV). Our recent study demonstrated that the Wnt pathway is also over-activated in the laser-induced CNV model, and blockade of Wnt signaling attenuated NV in Vldlr-/- mice and the laser-induced CNV. This project will extend our ongoing studies and use Wnt signaling reporter mice to further verify the activation of Wnt signaling in the retina and RPE of Vldlr-/- mice and laser-induced CNV model. We will also knockout ß-catenin, an essential effector of Wnt signaling, in the RPE to determine if interruption of Wnt signaling attenuates NV in these models. These studies will establish the pathogenic role of aberrant regulation of Wnt signaling in CNV and reveal a novel therapeutic target. There are two major alternative splicing variants of VLDLR, VLDLR1 and VLDLR2. Our preliminary data showed that the retina expresses exclusively VLDLR2 which has higher ectodomain shedding into the extracellular space than VLDLR1. VLDLR2 is known to have lower affinity to VLDL, and its function in the retina is unclear. We will test the hypothesis that soluble VLDLR ectodomain (sVLDLRN) shed into the extracellular space and circulation may function as a soluble inhibitor of Wnt signaling and modulates Wnt signaling through dimerization with LRP6, an essential co-receptor in the Wnt pathway. The inhibitory effects of sVLDLRN and its deletion peptide fragments on Wnt signaling and on CNV will be evaluated in vitro and in vivo. This project will investigate if VLDLR2 has more potent inhibition of Wnt signaling, compared to VLDLR1, due to its higher ectodomain shedding. These studies will reveal a new function of VLDLR2 in the retina. This project will establish the receptor ectodomain shedding and receptor:receptor dimerization as a new mechanism for modulation of the Wnt pathway. The proposed studies will also explore a novel pathogenic mechanism for CNV in AMD models and reveal a new therapeutic target. Identification of the peptide fragment of VLDLR with anti-angiogenic activity in this project has potential to develop a therapeutic drug for CNV.


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: 2022 ( Subtotal = $0 )
2022	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	10	10/13/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $333,000 )
2019	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	10	8/2/2019	NON-COMPETING CONTINUATION	$333,000
														Subtotal = $333,000

Issue Date FY: 2018 ( Subtotal = $333,000 )
2018	2018	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	9	6/1/2018	NON-COMPETING CONTINUATION	$333,000
														Subtotal = $333,000

Issue Date FY: 2017 ( Subtotal = $333,000 )
2017	2017	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	002	8	6/21/2017	NON-COMPETING CONTINUATION	$333,000
2017	2016	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	001	7	11/18/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$130,528
2017	2015	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Vision Research	000	6	11/18/2016	COMPETING CONTINUATION	-$130,528
														Subtotal = $333,000

Issue Date FY: 2016 ( Subtotal = $333,000 )
2016	2016	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73126	OKLAHOMA	USA	Vision Research	002	7	8/25/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$333,000
2016	2016	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73126	OKLAHOMA	USA	Vision Research	001	7	8/17/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$333,000
2016	2016	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73126	OKLAHOMA	USA	Vision Research	000	7	6/21/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$333,000
														Subtotal = $333,000

Issue Date FY: 2015 ( Subtotal = $333,000 )
2015	2015	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	001	6	5/19/2015	COMPETING CONTINUATION	$333,000
2015	2013	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	5	5/14/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $333,000

Issue Date FY: 2013 ( Subtotal = $448,496 )
2013	2013	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	5	7/19/2013	NON-COMPETING CONTINUATION	$448,496
														Subtotal = $448,496

Issue Date FY: 2012 ( Subtotal = $491,503 )
2012	2012	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	001	3	5/28/2012	SUPPLEMENT FOR EXPANSION	-$221
2012	2012	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	002	4	7/26/2012	NON-COMPETING CONTINUATION	$448,496
2012	2012	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	3	4/6/2012	SUPPLEMENT FOR EXPANSION	$43,228
														Subtotal = $491,503

Issue Date FY: 2011 ( Subtotal = $370,000 )
2011	2011	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	001	3	7/29/2011	COMPETING CONTINUATION	$370,000
2011	2010	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Trans-NIH Recovery Act Research Support	000	2	7/27/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,000

Issue Date FY: 2010 ( Subtotal = $366,250 )
2010	2010	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Trans-NIH Recovery Act Research Support	000	2	7/15/2010	NON-COMPETING CONTINUATION	$366,250
														Subtotal = $366,250

Issue Date FY: 2009 ( Subtotal = $366,250 )
2009	2009	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Trans-NIH Recovery Act Research Support	000	1	7/16/2009	NEW	$366,250
														Subtotal = $366,250

Grand Total All Awards = $3,707,499

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The role of the Wnt signaling pathway in choroidal neovascularization

Award Number: R01EY018659

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2021

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