Loss of optic nerve axons and the development of optic nerve head cupping are common to all forms of glaucoma. Recent studies have identified increased matrix metalloproteinases (MMPs) within the glaucomatous optic nerve head. As MMPs are known mediators of tissue remodeling, this could be important in the mechanism of optic axon loss and gliosis that occur in glaucoma. We have developed methods to measure mouse intraocular pressure and to produce chronic elevation of lOP in the mouse eye that induces optic nerve axon loss. We propose to use this experimental system to characterize MMP changes in the retina and at the optic nerve head following lOP elevation and to determine their relationship to optic nerve axon loss and gliosis. Key in these studies will be the use of transgenic mouse models to investigate mechanisms of MMP regulation and substrates of MMP action.
SPECIFIC AIMS : 1. To directly determine the identity and time course of MMP changes at the mouse optic nerve head following experimental lOP elevation. These studies will analyze MMP gene expression, protein expression and enzymatic activation. 2. To determine if the absence of MMP inhibition by endogenous inhibitors will increase optic nerve axon loss and increase gliosis in the optic nerve following experimental ocular hypertension. These studies will investigate TIMP-1 knockout mice and TIMP-2 knockout mice. 3. To determine if inhibition or elimination of MMP activity will reduce optic nerve axon loss and reduce gliosis in the optic nerve following experimental ocular hypertension. These studies will investigate MMP-9 knockout mice and a drug that inhibits MMP activity.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY014661-01A2
Application #
6867542
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Liberman, Ellen S
Project Start
2005-06-01
Project End
2009-03-31
Budget Start
2005-06-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$346,388
Indirect Cost
Name
University of California San Diego
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lindsey, James D; Grob, Seanna R; Scadeng, Miriam et al. (2013) Ocular integrity following manganese labeling of the visual system for MRI. Magn Reson Imaging 31:865-74
Leung, C K S; Lindsey, J D; Chen, L et al. (2009) Longitudinal profile of retinal ganglion cell damage assessed with blue-light confocal scanning laser ophthalmoscopy after ischaemic reperfusion injury. Br J Ophthalmol 93:964-8
Ju, Won-Kyu; Kim, Keun-Young; Angert, Mila et al. (2009) Memantine blocks mitochondrial OPA1 and cytochrome c release and subsequent apoptotic cell death in glaucomatous retina. Invest Ophthalmol Vis Sci 50:707-16
Ju, Won-Kyu; Kim, Keun-Young; Lindsey, James D et al. (2008) Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve. Invest Ophthalmol Vis Sci 49:4903-11
Leung, Christopher Kai-shun; Lindsey, James D; Crowston, Jonathan G et al. (2008) Longitudinal profile of retinal ganglion cell damage after optic nerve crush with blue-light confocal scanning laser ophthalmoscopy. Invest Ophthalmol Vis Sci 49:4898-902
Leung, Christopher K S; Lindsey, James D; Crowston, Jonathan G et al. (2008) In vivo imaging of murine retinal ganglion cells. J Neurosci Methods 168:475-8
Lindsey, James D; Weinreb, Robert N (2005) Elevated intraocular pressure and transgenic applications in the mouse. J Glaucoma 14:318-20
Weinreb, Robert N; Lindsey, James D (2005) The importance of models in glaucoma research. J Glaucoma 14:302-4