Corneal neovascularization (NV) is a major cause of blindness worldwide. Toward the overall goal of identifying a molecular target for blocking corneal NV, the objective of the proposed research is to determine the role of membrane type 1 matrix metalloproteinase (MT1-MMP) activity, and specifically its proteolytic functions, in corneal NV. Our laboratory has found that MT1-MMP increases vascular endothelial growth factor (VEGF)-A?induced ERK phosphorylation in a time- and concentration-dependent manner in vascular endothelial cells. Aortic ring assays showed diminished vessel sprouting in vitro in response to VEGF-A stimulation, but not to basic fibroblast growth factor (bFGF) stimulation, in mice with conditional deletion of vascular MT1-MMP as compared to that in control mice. In addition, diminished VEGF-A?induced corneal angiogenesis was seen in vivo in mice with conditional deletion of vascular MT1-MMP compared with that in control mice. We hypothesize that limbal microvascular endothelial cell-associated MT1-MMP is required for VEGF-A?mediated corneal NV and that MT1-MMP promotes corneal NV by three novel mechanisms: (i) MT1-MMP binds to, and degrades, VEGF receptor 1 (VEGFR1) on limbal microvascular endothelial cells (Aim A); (ii) MT1-MMP degradation of VEGFR1 on invading limbal microvascular endothelial cells potentiates pro-MMP2 activation and thereby increases its collagenolytic activity (Aim B); and (iii) enzymatically-active MT1-MMP tethered to stromal fibroblast-derived exosomes promotes VEGFR1 degradation on limbal vascular endothelial cells (Aim C). Spatial and temporal characterization of MT1-MMP activity in corneal angiogenesis and evaluation of the proposed mechanisms of corneal NV will be valuable for the treatment of corneal NV and for identifying potential targets for therapeutic intervention in ocular and systemic conditions involving angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY010101-21
Application #
9239470
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (91)S)
Program Officer
Mckie, George Ann
Project Start
1993-12-01
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
21
Fiscal Year
2017
Total Cost
$399,750
Indirect Cost
$149,750
Name
University of Illinois at Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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