Molecular Mechanisms of Sigma Receptor 1-Mediated Neuroprotection

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DESCRIPTION (provided by applicant): The general purpose of this proposal is to provide the principle investigator (PI) with the experience and skills necessary to become a successful and independent vision researcher. My long-term goal is to develop an independent research program directed toward discovery of treatments for glaucoma. Glaucoma is an age-related optic neuropathy that results in the death of retinal ganglion cells (RGCs) within the optic nerve. In this application, we propose to test whether ligands for a novel target, the molecular chaperone protein sigma receptor 1(CR1), can protect RGCs from death under conditions of glaucomatous stress. Several models of glaucoma have implicated tumor necrosis factor (TNF1) as a stressor that causes RGC death in glaucoma. We will use in vitro and in vivo model systems to test the hypothesis that CR1 protects RGCs by suppressing retinal glial cell release of TNF1 and by altering the signaling response of RGCs to TNF1. We will use a recently discovered rodent model for inducing increased intraocular pressure and knockout mouse technology to test our hypothesis.The following three aims will be addressed: 1) Test the hypothesis that CR1 ligands modulate glial inflammatory responses using in vitro model systems. 2) Test the hypothesis that CR1 activation shifts the balance of TNF1 mediated signaling towards survival within RGCs. 3) Test the hypothesis that CR1 activation alters glial and neuronal responses to ocular hypertension and that CR1 ligand will suppress glial activation and protect against RGC death in an in vivo model of glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is the second leading cause of blindness worldwide. Because of the aging population, approximately 80 million people will be afflicted with this disease by the year 2020. A major risk factor for glaucoma is increased intraocular pressure (IOP), and this is currently the only modifiable risk factor. However, treatments that lower IOP can cause vision-threatening complications. In addition, studies indicate that progression of optic nerve degeneration continues in as many as 50% of patients treated with standard IOP-lowering therapy. Therefore, new neuroprotective targets for preventing glaucomatous vision loss are needed. This proposal tests a novel target for glaucoma treatment!