Corneal neovascularization (NV) is a common, disabling condition and a major cause of blindness that can follow corneal injury or infection. Our long term goal is to characterize the role of VEGF receptors in the two central corneal vascularization processes, vascular angiogenesis (VA) and lymphangiogenesis (LA). The involvement of the epithelial, soluble form of VEGFR-2 (sVEGFR-2) in LA has been well characterized. However, the role of membrane- bound, vascular VEGFR-2 (mbVEGFR-2) in corneal VA and LA has not. These proposed experiments are designed to characterize the potential angiogenic and lymphangiogenic roles of the membrane bound isoform of VEGFR-2. We propose the hypothesis that vascular mbVEGFR2 may have distinct roles, separate from those of VEGFR1 or VEGFR3, in response to induction by VEGF-A (towards VA) or VEGF-C (towards LA) in corneal angiogenesis/ lymphangiogenesis.
Two specific aims have been proposed to characterize the role of VEGFR- 2 in corneal angiogenesis and lymphangiogenesis.
Aim A. Use inducible, conditional knockout mouse lines to determine whether mbVEGFR2 maintains a counterbalanced relationship with sVEGFR1 and sVEGFR2 in the cornea.
Aim B. Characterize the individual roles of pro- angiogenic agents on VEGFR activity and VA/LA initiation, progression, and maintenance. SIGNIFICANCE: The endothelial receptor mbVEGFR2 sits at the crossroads of VA/LA initiation. Our proposed research strategy will define the role mbVEGFR2 plays in maintaining the vascular/avascular balance at the corneal border in both the normal and injured eye, increase our understanding of the VEGFR2-R3 relationship, and separate the relative contributions of pro-angiogenic agents and mbVEGFR2 to proliferation, migration, and tube formation. A better understanding of the role this receptor plays in both the normal and injured eye is of clinical importance because it increases our ability to develop therapeutic methods to prevent or reverse pathological VA and LA in the cornea, in other transplant procedures, and in tumor growth and metastasis.

Public Health Relevance

Angiogenesis and lymphangiogenesis are the processes that increase production of blood and lymphatic vessels;both can be physiologically necessary and pathological. We hypothesize that VEGFR-2 plays an important role in the regulation of corneal angiogenesis and lymphangiogenesis. Understanding the molecular mechanisms of corneal angiogenesis and lymphangiogenesis will provide novel therapeutic interventions in the treatment of angiogenesis and lymphangiogenesis-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY023691-02
Application #
8702186
Study Section
(DPVS)
Program Officer
Mckie, George Ann
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Zhong, Wei; Montana, Mario; Santosa, Samuel M et al. (2018) Angiogenesis and lymphangiogenesis in corneal transplantation-A review. Surv Ophthalmol 63:453-479
Yamakawa, Michael; Doh, Susan J; Santosa, Samuel M et al. (2018) Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review. Med Res Rev 38:1769-1798
Zhong, Wei; Gao, Xinbo; Wang, Shuangyong et al. (2017) Prox1-GFP/Flt1-DsRed transgenic mice: an animal model for simultaneous live imaging of angiogenesis and lymphangiogenesis. Angiogenesis 20:581-598
Chang, Jin-Hong; Putra, Ilham; Huang, Yu-Hui et al. (2016) Limited versus total epithelial debridement ocular surface injury: Live fluorescence imaging of hemangiogenesis and lymphangiogenesis in Prox1-GFP/Flk1::Myr-mCherry mice. Biochim Biophys Acta 1860:2148-56
Han, Kyu-Yeon; Chang, Jin-Hong; Lee, Hyun et al. (2016) Proangiogenic Interactions of Vascular Endothelial MMP14 With VEGF Receptor 1 in VEGFA-Mediated Corneal Angiogenesis. Invest Ophthalmol Vis Sci 57:3313-22
Chang, Jin-Hong; Huang, Yu-Hui; Cunningham, Christy M et al. (2016) Matrix metalloproteinase 14 modulates signal transduction and angiogenesis in the cornea. Surv Ophthalmol 61:478-97
Yang, Jessica F; Walia, Amit; Huang, Yu-hui et al. (2016) Understanding lymphangiogenesis in knockout models, the cornea, and ocular diseases for the development of therapeutic interventions. Surv Ophthalmol 61:272-96
Park, Paul J; Chang, Michael; Garg, Nitin et al. (2015) Corneal lymphangiogenesis in herpetic stromal keratitis. Surv Ophthalmol 60:60-71
Han, Kyu-Yeon; Chang, Michael; Ying, Hong-Yu et al. (2015) Selective Binding of Endostatin Peptide 4 to Recombinant VEGF Receptor 3 In Vitro. Protein Pept Lett 22:1025-30
Han, Kyu-Yeon; Dugas-Ford, Jennifer; Lee, Hyun et al. (2015) MMP14 Cleavage of VEGFR1 in the Cornea Leads to a VEGF-Trap Antiangiogenic Effect. Invest Ophthalmol Vis Sci 56:5450-6

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