Enhancing retinal ganglion cell (RGC) survival in primary open-angle glaucoma is the fundamental treatment goal for patients with this disease, but to date, attempts to reduce intraocular pressure (IOP) secondary to surgery or drugs is the only clinically-approved approach. Primary neuroprotective therapies that directly protect RGCs from glaucomatous injury are desired, but have yet to be advanced to the clinic, largely because the complex, pan-cellular pathology that defines this disease will likely require a pleiotropic therapy capable of acting on multiple injury mechanisms concomitantly. Inducing an adaptive, multi-factorial conditioning response by a noninjurious stress may represent one such therapeutic approach, given its track record of demonstrated efficacy in preclinical models of retinal ischemia and phototoxicity, and the run of clinical trials of conditioning for myocardial ischemia and stroke. In fact, we recently showed that exposing mice to a series of mild systemic hypoxic stresses prior to inducing a 3-wk period of experimental glaucoma afforded robust protection of RGC soma and axons. Preliminary functional and morphologic findings provided herein document similarly robust protection even when the repetitive hypoxic stimulus is presented after disease onset. This epigenetic response to glaucoma postconditioning forms the basis of the present application, and our studies will be guided by the following specific aims.
Specific Aim 1 : Using our inducible model of experimental glaucoma, test the hypothesis that the structural and functional protection afforded RGCs by repetitive hypoxic postconditioning (HX-Post) is sustained as the disease and treatment progress.
Specific Aim 2 : In our inducible glaucoma model, test the related hypothesis that repetitive pharmacologic postconditioning with the clinically-approved drug deferroxamine (DFX-Post) will also afford sustained morphologic and functional protection of RGCs. The hypothesis that DFX protects RGCs via stabilization of the transcription factor hypoxia-inducible factor-1? (HIF-1?) will alsobe tested.
Specific Aim 3 : In the DBA/2J genetic model of glaucoma, test the hypotheses that HX-Post, and DFX-post, administered between 7.5-12.0 months of age, will positively impact 'end-stage' RGC disease phenotypes (structural and functional, somal and axonal).
Specific Aim 4 : Using genetic and pharmacologic approaches, test in our inducible model the hypothesis that HX-Post-mediated is critically dependent on the HIF-1? gene target CCL2 (MCP-1). Documenting sustained improvements in RGC function and structure in two distinct glaucoma models secondary to repetitive physiologic or pharmacologic postconditioning will provide strong proof-of-concept, translationally-promising evidence for the notion that a spectrum of innate epigenetics-based protective responses, some of which we will reveal here, can be activated for RGC protection in human glaucoma.
Retinal ganglion cell death in glaucoma is responsible for devastating vision loss in millions of Americans. Our proposed work provides a new epigenetics-based approach to retinal ganglion cell protection, which involves exposing the individual to noninjurious stress stimuli that will alter endogenous gene and protein expression to promote retinal ganglion cell survival. Demonstrating that these innate cytoprotective pathways can reduce or prevent retinal ganglion cell injury, and associated vision loss, even when activated after disease onset, will provide new therapeutic options for treating patients with glaucoma and other optic neuropathies.
|Gidday, Jeffrey M; Zhang, Lihong; Chiang, Chia-Wen et al. (2015) Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset. Neurotherapeutics 12:502-14|
|Zhu, Yanli; Zhang, Lihong; Gidday, Jeffrey M (2013) Role of hypoxia-inducible factor-1Î± in preconditioning-induced protection of retinal ganglion cells in glaucoma. Mol Vis 19:2360-72|
|Zhu, Yanli; Zhang, Lihong; Sasaki, Yo et al. (2013) Protection of mouse retinal ganglion cell axons and soma from glaucomatous and ischemic injury by cytoplasmic overexpression of Nmnat1. Invest Ophthalmol Vis Sci 54:25-36|
|Zhu, Yanli; Zhang, Lihong; Schmidt, Jimena F et al. (2012) Glaucoma-induced degeneration of retinal ganglion cells prevented by hypoxic preconditioning: a model of glaucoma tolerance. Mol Med 18:697-706|