Retinal neovascularization is an important pathological feature of eye diseases such as diabetic retinopathy and age related macular degeneration. A precise spatial and temporal regulation of extracellular proteolysis is required for neovascularization. Tissue Inhibitor of Metalloproteinase-3 (TIMP-3), a regulator of matrix metalloproteinases (MMPs), is deposited by retinal pigment epithelial (RPE) cells into Bruch s membrane (BM) where it is a component of the extracellular matrix. Mutations in the TIMP-3 gene cause Sorsby s fundus dystrophy (SFD), an inherited from of blindness. SFD is of considerable interest as it is the only genetic disorder in which haemorrhagic macular degeneration occurs in the majority of patients. We have demonstrated that TIMP-3 is an inhibitor of angiogenesis. Since choroidal neovascularization is a prominent feature of SFD we propose that TIMP-3 mutations in SFD may affect it s angiostatic function. It is hypothesized that under normal physiological conditions, endothelial cells are maintained in a quiescent state because of regulated balance between angiogenesis inducers and inhibitors. We propose the following model: TIMP-3 in the BM efficiently inhibits neovascular invasion from the choriocapillaris by a) Inhibiting MMP activity, resulting in an intact matrix and sequestration of angiogenic factors within the matrix and/or b) Binding directly to the surface of endothelial cells to inhibit endothelial cell responses. During pathological retinal neovascularization as seen in SFD, mutant TIMP-3 is compromised in this inhibitory activity which results in neovascularization. We propose to test this model with the following specific aims: 1. To determine the mechanism by which TIMP-3 inhibits angiogenesis. 2. To determine the direct effect of mutated SFD TIMP-3 protein or endothelial cells and angiogenesis. 3. To determine the mechanism by which mutated SFD-TIMP-3 secreted by RPE cells regulates endothelial cell responses. The broad long term goal of this proposal is to gain an understanding of the mechanism(s) by which alterations in matrix integrity may regulate retinal neovascularization using TIMP-3 mutations in SFD as a model.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29EY012109-05
Application #
6518583
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
1998-03-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2005-02-28
Support Year
5
Fiscal Year
2002
Total Cost
$107,548
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Navarro, Angels; Anand-Apte, Bela; Parat, Marie-Odile (2004) A role for caveolae in cell migration. FASEB J 18:1801-11
Qi, Jian Hua; Ebrahem, Quteba; Moore, Nina et al. (2003) A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 9:407-15
Qi, Jian Hua; Ebrahem, Quteba; Anand-Apte, Bela (2003) Tissue inhibitor of metalloproteinases-3 and Sorsby fundus dystrophy. Adv Exp Med Biol 533:97-105
Qi, Jian Hua; Ebrahem, Quteba; Yeow, Karen et al. (2002) Expression of Sorsby's fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis. J Biol Chem 277:13394-400