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Role of VEGFR2 trafficking in pathological angiogenesis in age related macular degeneration

Award Number: R01EY029339
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Role of VEGFR2 trafficking in pathological angiogenesis in age related macular degeneration - ABSTRACT Wet age-related macular degeneration (AMD) is a leading cause of vision loss in old patients. In wet AMD, excessive vascular endothelial growth factor (VEGF) causes abnormal angiogenesis and vascular leakage, which in turn damages the retina. The overall goal of this proposal is to determine the mechanism how excessive VEGF induces transition from quiescent blood vessels to pathological leaky angiogenesis in wet AMD by studying the fundamental roles of VEGFR2 trafficking. Angiogenesis is restrained in quiescent healthy endothelial cells (ECs), where VEGFR2 trafficking is limited by the interaction with VE-cadherin at adherens junctions (AJs). In contrast, marked VEGFR2 trafficking is evident in angiogenic ECs, where VEGFR2 translocates to filopodia tips that extend towards the VEGF ligand. We provided the first evidence that VEGFR2 is directly transported by the kinesin-3 family protein, KIF13B, a microtubules plus-end motor, to filopodia of sprouting ECs. Based on our finding, we will test our central hypothesis that KIF13B mediates VEGFR2 trafficking away from AJs to induce AJ disassembly and vascular leakage, and the directional trafficking of VEGFR2 to filopodia induces pathological angiogenesis in response to excessive VEGF in wet AMD. Our Specific Aims will test the following hypotheses; 1) KIF13B-mediated VEGFR2 trafficking from AJs breaks the critical interaction between VEGFR2 and VE-cadherin involved in stabilizing AJs, thus induces AJ disassembly and vascular leakage. 2) VEGF signaling induces KIF13B-mediated directional trafficking of VEGFR2 to filopodia extending toward VEGF, and the trafficking is required for sprouting angiogenesis. 3) KIF13B-mediated VEGFR2 trafficking is pathogenesis in wet AMD, thus the inhibition of the trafficking is a promising strategy for the therapy of wet AMD. To rigorously test these hypotheses, our lab has generated powerful tools (genetic mouse models and peptide inhibitors) that have led to conceptual advances. EC specific KIF13B knockout mice display a selective angiogenic defect in the pathological setting. A small peptide inhibitor disrupting the KIF13B/VEGFR2 interaction, termed KAI, inhibited choroidal neovascularization (CNV) in wet AMD model in mice. Using these powerful tools, we will examine the roles of KIF13B in VEGF-induced permeability of ocular blood vessels, live imaging of directional VEGFR2 trafficking in choroidal sprouting ex vivo, and pathology of wet AMD, characterized by abnormal angiogenesis, vascular leakage, and inflammation, using laser-induced CNV model. If successful, our proposed studies provide the novel concept of angiogenesis regulation by targeting VEGFR2 trafficking.


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 = $0 )
2025	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Vision Research	000	5	8/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $399,750 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Vision Research	000	5	3/30/2023	NON-COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2022 ( Subtotal = $387,758 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Vision Research	000	4	3/31/2022	NON-COMPETING CONTINUATION	$387,758
														Subtotal = $387,758

Issue Date FY: 2021 ( Subtotal = $387,757 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Vision Research	000	3	3/22/2021	NON-COMPETING CONTINUATION	$387,757
														Subtotal = $387,757

Issue Date FY: 2020 ( Subtotal = $399,750 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Vision Research	000	2	4/2/2020	NON-COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2019 ( Subtotal = $399,750 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Vision Research	000	1	3/15/2019	NEW	$399,750
														Subtotal = $399,750

Grand Total All Awards = $1,974,765

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Role of VEGFR2 trafficking in pathological angiogenesis in age related macular degeneration

Award Number: R01EY029339

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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