Retinal ischemia is defined as an arrest of blood flow and reduction of oxygen supply to the retina. Ischemic damage to the retina is a common pathological factor in a number of blinding diseases in humans including central retinal artery and vein occlusions, diabetes, retinopathy of prematurity, and glaucoma to name a few. Although ischemia-induced damage to the retina is known to lead to irreversible loss of ganglion cells, the pathophysiology underlying this process is not clearly understood. The long-term goal of this laboratory is to determine the triggering mechanisms that lead to ganglion cell loss in retinal ischemia because a complete understanding of the disease process will help us in designing preventative strategies to rescue ganglion cells in sight-threatening ischemic retinal diseases. Preliminary findings, using a central retinal ligation model in mice, support the hypothesis that retinal ischemia induces expression of matrix metalloproteinase gelatinase B (MMP-9) by cells in the ganglion cell layer; that MMP-9 mediates degradation of extracellular matrix (ECM) composing of retinal inner limiting membrane (ILM); and that this leads to apoptosis of ganglion cells. Experiments are now proposed to determine (a) the timing and localization of MMPs in the ganglion cell layer, (b) the cell types that synthesize these MMPs in the ganglion cell layer, (c) the role of a particular MMP that leads to ganglion cell loss, (d) the ECM components that are degraded in the ILM, and (e) the neuroprotective effects of MMP inhibition on ganglion cell loss. The proposed studies would not only facilitate our understanding of the mechanisms that underlie ischemia-induced ganglion cell loss in this model system, but in the long-run would also help us in designing neuroprotective strategies to prevent loss of retinal ganglion cells in blinding ischemic retinal diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013643-04
Application #
6635745
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Hunter, Chyren
Project Start
2001-08-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
4
Fiscal Year
2003
Total Cost
$284,000
Indirect Cost
Name
Oakland University
Department
Type
Organized Research Units
DUNS #
041808262
City
Rochester
State
MI
Country
United States
Zip Code
48309
Lin, Song; Cheng, Mei; Dailey, Wendelin et al. (2009) Norrin attenuates protease-mediated death of transformed retinal ganglion cells. Mol Vis 15:26-37
Rock, Nathan; Chintala, Shravan K (2008) Mechanisms regulating plasminogen activators in transformed retinal ganglion cells. Exp Eye Res 86:492-9
Harvey, Ronee; Chintala, Shravan K (2007) Inhibition of plasminogen activators attenuates the death of differentiated retinal ganglion cells and stabilizes their neurite network in vitro. Invest Ophthalmol Vis Sci 48:1884-91
Chintala, Shravan K (2006) The emerging role of proteases in retinal ganglion cell death. Exp Eye Res 82:5-12
Chintala, Shravan K; Wang, Nan; Diskin, Shiri et al. (2005) Matrix metalloproteinase gelatinase B (MMP-9) is associated with leaking glaucoma filtering blebs. Exp Eye Res 81:429-36
Mali, Raghuveer S; Cheng, Mei; Chintala, Shravan K (2005) Intravitreous injection of a membrane depolarization agent causes retinal degeneration via matrix metalloproteinase-9. Invest Ophthalmol Vis Sci 46:2125-32
Mali, Raghuveer S; Cheng, Mei; Chintala, Shravan K (2005) Plasminogen activators promote excitotoxicity-induced retinal damage. FASEB J 19:1280-9
Zhang, Xu; Cheng, Mei; Chintala, Shravan K (2004) Optic nerve ligation leads to astrocyte-associated matrix metalloproteinase-9 induction in the mouse retina. Neurosci Lett 356:140-4
Zhang, Xu; Chintala, Shravan K (2004) Influence of interleukin-1 beta induction and mitogen-activated protein kinase phosphorylation on optic nerve ligation-induced matrix metalloproteinase-9 activation in the retina. Exp Eye Res 78:849-60
Zhang, Xu; Cheng, Mei; Chintala, Shravan K (2004) Kainic acid-mediated upregulation of matrix metalloproteinase-9 promotes retinal degeneration. Invest Ophthalmol Vis Sci 45:2374-83

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