Molecular Mechanisms of Sigma Receptor 1-Mediated Neuroprotection

Project Summary: 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(?R1), can protect RGCs from death under conditions of glaucomatous stress. Several models of glaucoma have implicated tumor necrosis factor (TNF?) as a stressor that causes RGC death in glaucoma. We will use in vitro and in vivo model systems to test the hypothesis that ?R1 protects RGCs by suppressing retinal glial cell release of TNF? and by altering the signaling response of RGCs to TNF?. 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 ?R1 ligands modulate glial inflammatory responses using in vitro model systems. 2) Test the hypothesis that ?R1 activation shifts the balance of TNF? mediated signaling towards survival within RGCs. 3) Test the hypothesis that ?R1 activation alters glial and neuronal responses to ocular hypertension and that ?R1 ligand will suppress glial activation and protect against RGC death in an in vivo model of glaucoma.