Thursday, March 13, 2025
3/13/2025
PROJECT SUMMARY Normal tension glaucoma (NTG) is characterized by optic neuropathy with progressive retinal ganglion cell (RGC) death and optic nerve (ON) degeneration but in the absence of intraocular pressure (IOP) elevation. All current glaucoma treatments are to lower IOP and are less effective in NTG patients. The primary reasons for the therapeutic vacuum are the limited understanding of the molecular mechanisms of IOP-independent glaucomatous degeneration and the lack of a practical and effective NTG animal model. Causal mutations in the optineurin gene (OPTN) have been found in familial and sporadic NTG. Interestingly, OPTN mutations also cause inherited forms of another CNS axonopathy, amyotrophic lateral sclerosis (ALS), indicating a common degenerative machinery that can be activated by dysfunctional OPTN in vulnerable CNS neuronal populations. However, although OPTN has been extensively studied and its various roles in autophagy, cytokine signaling, and vesicle trafficking have been found, the pathophysiology role of OPTN in CNS neurodegeneration are far from clear. We have recently established a highly efficient NTG mouse model by truncating OPTN gene in RGCs specifically, which presents significant RGCs and ON degeneration within weeks. Using this novel NTG model, we propose to investigate how OPTN mutation causes neurodegeneration in vivo through validating and characterizing OPTN-interacting proteins in RGCs and ON. Through these studies, we will generate essential information to uncover novel molecular mechanisms of glaucomatous neurodegeneration related with OPTN that may be also shared by ALS and other CNS axonopathies, identify novel modifiers of RGC/ON neurodegeneration, and provide valuable tools and animal models to develop neuroprotection therapies.
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