The long-term objective of our research is to develop a neuroprotective strategy that will complement the current treatment of glaucoma with IOP reduction. Our hypothesis is that long-term pharmacological induction of Hsp72 (the inducible form of heat shock protein 70) expression can protect RGCs from glaucomatous damage. This hypothesis is based on the wide range of cytoprotective capacities of HSP72, which may be explained by its ability to inhibit several apoptotic pathways.
Specific aims of the proposal are:
Aim 1. Determine the effect of Hsp72 overexpression on RGC survival in a rat glaucoma model. Adeno- associated viral (AAV, serotype 5) based vectors carrying the HSP72 gene (AAV-HSP72) will be used to deliver and express the corresponding protein in RGCs, which is the primary target for neuroprotection. Specific overexpression of HSP72 in glaucomatous retinas will allow us to evaluate its neuroprotective effect.
Aim 2. Elucidate the mechanisms of inhibition of apoptotic pathways by HSP72 in experimental glaucoma. HSP72 is known to inhibit multiple pathways leading to cell death and its anti-apoptotic functions are associated with binding to apoptosis protease activating factor-1 (Apaf-1), apotosis-inducing factor (AIF) and c-Jun N-terminal kinase (JNK). The involvement of these and other potential mechanisms of RGC protection by HSP72 in experimental glaucoma will be studied. The results of these studies will help us define HSP72 neuroprotective mechanisms and better understand RGC apoptosis in glaucoma.
Aim 3. Evaluate the therapeutic potential of pharmacological induction of HSP72 for glaucoma. We will study GGA and arimoclomol, HSP72 co-inducers, as potential therapeutic agents for protection of RGCs in the rat glaucoma model. The role of HSP72 in GGA and arimoclomol mediated neuroprotection will be analyzed by inhibition of HSP72 expression with small interfering RNA (siRNA) designed to degrade HSP72 mRNA. The proposal is intended to comprehensively evaluate the Hsp72 neuroprotective effect in experimental glaucoma and understand the mechanisms of its action on apoptotic pathways. We believe that the cytoprotective and anti-apoptotic characteristics of HSP72 and the possibility to pharmacologically induce expression of this protein in cells experiencing stress make this protein an attractive therapeutic target for glaucoma neuroprotection. The ability of HSP72 to protect cells from a variety of stress stimuli is an important factor in designing a strategy to preserve RGCs in glaucoma, since the cellular damage in this disease may be caused by different molecular mechanisms that have a common final pathway of characteristic optic nerve damage and visual loss.

Public Health Relevance

The degeneration of retinal ganglion cells (RGCs) is the primary cause of visual loss in glaucoma, which affects more than 70 million people worldwide. The main aim of the proposed study is the evaluation of the heat shock protein 72 (HSP72) induction with non-toxic drugs in RGC protection in animals with glaucoma. This protein is known to protect different types of cells, including neuronal cells, against various insults. The results of our studies may provide support for therapeutic consideration of HSP72 inducers as potential neuroprotective drugs for glaucoma.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Chin, Hemin R
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Piri, Natik; Kwong, Jacky M K; Gu, Lei et al. (2016) Heat shock proteins in the retina: Focus on HSP70 and alpha crystallins in ganglion cell survival. Prog Retin Eye Res 52:22-46
Kyung, Haksu; Kwong, Jacky M K; Bekerman, Vlad et al. (2015) Celastrol supports survival of retinal ganglion cells injured by optic nerve crush. Brain Res 1609:21-30
Kwong, J M K; Gu, L; Nassiri, N et al. (2015) AAV-mediated and pharmacological induction of Hsp70 expression stimulates survival of retinal ganglion cells following axonal injury. Gene Ther 22:138-45
Kim, Joon Mo; Kyung, Haksu; Shim, Seong Hee et al. (2015) Location of Initial Visual Field Defects in Glaucoma and Their Modes of Deterioration. Invest Ophthalmol Vis Sci 56:7956-62
Kwong, Jacky M K; Hoang, Celia; Dukes, Reshil T et al. (2014) Bis(zinc-dipicolylamine), Zn-DPA, a new marker for apoptosis. Invest Ophthalmol Vis Sci 55:4913-21
Bitrian, Elena; Song, Brian J; Caprioli, Joseph (2014) Bleb revision for resolution of hypotony maculopathy following primary trabeculectomy. Am J Ophthalmol 158:597-604.e1
Kwong, Jacky M K; Vo, Nancy; Quan, Ann et al. (2013) The dark phase intraocular pressure elevation and retinal ganglion cell degeneration in a rat model of experimental glaucoma. Exp Eye Res 112:21-8
Piri, Natik; Kwong, Jacky M K; Caprioli, Joseph (2013) Crystallins in retinal ganglion cell survival and regeneration. Mol Neurobiol 48:819-28
Munemasa, Yasunari; Chang, Chang-Sheng; Kwong, Jacky M K et al. (2012) The neuronal EGF-related gene Nell2 interacts with Macf1 and supports survival of retinal ganglion cells after optic nerve injury. PLoS One 7:e34810
Law, Simon K; Sami, Maha; Piri, Natik et al. (2011) Asymmetric phenotype of Axenfeld-Rieger anomaly and aniridia associated with a novel PITX2 mutation. Mol Vis 17:1231-8

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