Retinal neovascularization is a major cause of blindness, and therefore improvements in our understanding of the molecular mechanism underlying this disease are needed to provide better options for treatment. This proposal focuses on understanding the role of two membrane-anchored metalloproteases, ADAMs (a disintegrin and metalloprotease) 9 and 15, in pathological neovascularization in the retina. We have shown that adam 15-/- mice have strongly decreased pathological neovascularization in a model for retinopathy of prematurity (ROP model), whereas adam 9-/- mice, and adam 9/15-/- double knockout mice have strongly increased pathological neovascularization compared to wildtype controls. We now wish to understand the mechanism underlying the role of ADAMs 9 and 15 in proliferative retinopathy. Specifically, we will: i) Identify whether the metalloprotease domain or other domains of ADAMs 9 or 15 are critical for their role in pathological neovascularization using """"""""knock-in"""""""" mice. The metalloprotease domain of ADAMs 9 and 15 may be involved in cleaving substrate proteins, the disintegrin domain/cysteine-rich region may function in cell-cell and cell matrix interactions, and the cytoplasmic domain may have a role in signaling. We will generate """"""""knock-in"""""""" mice to evaluate the contribution of different domains to neovascularization. ii) Search for potential substrates or interacting partners of ADAMs 9 and 15 that may be relevant for pathological neovascularization. The most likely hypothesis is that ADAM 9 and ADAM 15 cleave substrate oroteins with a role in angiogenesis. Protein ectodomain shedding is a well-established functional regulator of proteins such as TNFa, EGF-receptor ligands, and Notch and Delta. We will therefore test whether ADAMs 9 or 15, or other ADAMs cleave molecules with a role in angiogenesis, such as VEGFR-2, Tie-1 and 2, PECAM, VE-cadherin, etc. However, should """"""""knock-in"""""""" mice demonstrate that regulation of angiogenesis is not due to the metalloprotease activity of ADAM 9 and 15, we will search for functionally relevant extracellular or cytoplasmic interacting proteins. Since ADAMs 9 and 15 are not required for normal development and adult homeostasis, we anticipate that the proposed studies will provide new targets for the design of drugs that regulate pathological neovascularization without affecting normal angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015719-04
Application #
7123818
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2004-09-06
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$513,692
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
Glomski, Krzysztof; Monette, Sébastien; Manova, Katia et al. (2011) Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures. Blood 118:1163-74
Maretzky, Thorsten; Evers, Astrid; Zhou, Wenhui et al. (2011) Migration of growth factor-stimulated epithelial and endothelial cells depends on EGFR transactivation by ADAM17. Nat Commun 2:229
Blobel, Carl P (2010) 3D trumps 2D when studying endothelial cells. Blood 115:5128-30
Hassemer, E L; Le Gall, S M; Liegel, R et al. (2010) The waved with open eyelids (woe) locus is a hypomorphic mouse mutation in Adam17. Genetics 185:245-55
Mendelson, Karen; Swendeman, Steven; Saftig, Paul et al. (2010) Stimulation of platelet-derived growth factor receptor beta (PDGFRbeta) activates ADAM17 and promotes metalloproteinase-dependent cross-talk between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling pathways. J Biol Chem 285:25024-32
Jorissen, Ellen; Prox, Johannes; Bernreuther, Christian et al. (2010) The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J Neurosci 30:4833-44
Guaiquil, Victor H; Swendeman, Steven; Zhou, Wenhui et al. (2010) ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice. J Mol Med (Berl) 88:497-505
Weskamp, Gisela; Mendelson, Karen; Swendeman, Steve et al. (2010) Pathological neovascularization is reduced by inactivation of ADAM17 in endothelial cells but not in pericytes. Circ Res 106:932-40
Parry, David A; Toomes, Carmel; Bida, Lina et al. (2009) Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice. Am J Hum Genet 84:683-91
Guaiquil, Victor; Swendeman, Steven; Yoshida, Tsunehiko et al. (2009) ADAM9 is involved in pathological retinal neovascularization. Mol Cell Biol 29:2694-703

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