Retinal ischemia is a serious and common clinical problem. It occurs as a result of acute vascular occlusion and it is a pathogenetic mechanism of the visual loss that occurs in a number of ocular diseases such as acute glaucoma, diabetic retinopathy and hypertensive vascular disease. Our long-range goal is to enhance our understanding of the fundamental mechanisms by which ischemia causes retinal damage. Based upon the knowledge acquired, strategies to improve retinal viability will be developed and tested in in vivo animal models resembling human diseases. The pathophysiology of ischemic retinal damage is complex and appears to involve several mechanisms of cell death. During the first 4 years of this project, extensive morphological, biochemical, immunohistochemical, pharmacologic and genetic evidence for apoptotic cell death as a consequence of ischemia has been obtained. Additionally, we have obtained data demonstrating that strategies aimed at inhibiting apoptosis attenuate retinal injury as a consequence of ischemia. Based on these findings in retinal ischemia as well as data derived from our parallel studies in cerebral ischemia, we now propose to focus further on the role of apoptotic cell death in retinal ischemia, with particular emphasis on caspases. The caspases comprise a family of cysteine proteases which are considered to be the central executioners of the apoptotic pathway in all metazoan cells. Despite the enormous progress in our knowledge of the cellular mechanisms of apoptosis, the apoptotic pathways triggered by retinal ischemia are only beginning to be unraveled.
The specific aims of this project are to test the following hypotheses using a clinically relevant animal model of transient retinal ischemia: (1) Retinal ischemia can activate multiple apoptotic pathways. (a) Caspase activation may be triggered by the """"""""intrinsic"""""""" (mitochondria-mediated) cell death pathway in response to retinal ischemia. (b) Caspase activation may be triggered by the """"""""extrinsic"""""""" (death receptor-mediated) cell death pathway mediated by fasL and/or TNF-alpha in response to retinal ischemia. (2) Retinal ischemic injury may be prevented or attenuated by agents which inhibit apoptosis. (a) Preconditioning, an endogenously-based treatment strategy affords protection by inhibiting caspase activation. (b) Multi-modal therapy employing caspase inhibitor(s) and anti-excitotoxic strategies work synergistically toreduce ischemic retinal damage.
| David, Joel; Melamud, Aleksandr; Kesner, Leo et al. (2011) A novel calpain inhibitor for treatment of transient retinal ischemia in the rat. Neuroreport 22:633-6 |
| Malhotra, Samit; Naggar, Isaac; Stewart, Mark et al. (2011) Neurogenic pathway mediated remote preconditioning protects the brain from transient focal ischemic injury. Brain Res 1386:184-90 |
| Rosenbaum, Daniel M; Degterev, Alexei; David, Joel et al. (2010) Necroptosis, a novel form of caspase-independent cell death, contributes to neuronal damage in a retinal ischemia-reperfusion injury model. J Neurosci Res 88:1569-76 |
| Dreixler, John C; Hemmert, Jonathan W; Shenoy, Shanti K et al. (2009) The role of Akt/protein kinase B subtypes in retinal ischemic preconditioning. Exp Eye Res 88:512-21 |
| Berger, Samuel; Savitz, Sean I; Nijhawan, Sheetal et al. (2008) Deleterious role of TNF-alpha in retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci 49:3605-10 |
| Jasmin, Jean-Francois; Malhotra, Samit; Singh Dhallu, Manjeet et al. (2007) Caveolin-1 deficiency increases cerebral ischemic injury. Circ Res 100:721-9 |
| Malhotra, Samit; Savitz, Sean I; Ocava, Lenore et al. (2006) Ischemic preconditioning is mediated by erythropoietin through PI-3 kinase signaling in an animal model of transient ischemic attack. J Neurosci Res 83:19-27 |
| Savitz, Sean I; Rosenbaum, Daniel M; Dinsmore, Jonathan H et al. (2002) Cell transplantation for stroke. Ann Neurol 52:266-75 |
| Zhang, Cheng; Rosenbaum, Daniel M; Shaikh, Afzhal R et al. (2002) Ischemic preconditioning attenuates apoptotic cell death in the rat retina. Invest Ophthalmol Vis Sci 43:3059-66 |
| Rosenbaum, D M; Rosenbaum, P S; Singh, M et al. (2001) Functional and morphologic comparison of two methods to produce transient retinal ischemia in the rat. J Neuroophthalmol 21:62-8 |
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