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Principal Investigator: Yang Hu
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $545,696
Funding agency: National Eye Institute
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.
Terms: <Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Animal Model><Animal Models and Related Studies><Assay><Autophagocytosis><Axon><Axonal Transport><Axoplasmic Transport><Bioassay><Biochemical><Biological Assay><Biotin><Blindness><Cell Death><Collaborations><Cranial Nerve II><Cranial Nerve II Diseases><Cranial Nerve II Disorder><Cytokine Signal Transduction><Cytokine Signaling><Data><Dysfunction><Environment><Failure><Functional disorder><Gehrig's Disease><Gene Alteration><Gene Mutation><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glaucoma><Goals><Hereditary><Histologic><Histologically><Human><Hybrids><Image><Impairment><Inherited><Intervention><Intervention Strategies><Intraocular Pressure><Link><Lou Gehrig Disease><Mediating><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular><Monitor><Morphology><Murine><Mus><Mutation><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neural-Optical Lesion><Neurocyte><Neuron Degeneration><Neurons><Ocular Hypertension><Ocular Tension><Optic Nerve><Optic Nerve Diseases><Optic Neuropathy><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Phenotype><Physiologic Intraocular Pressure><Physiopathology><Play><Population><Position><Positioning Attribute><Proteins><Receptor Protein><Retina><Retinal Ganglion Cells><Role><SNPH><Scientist><Second Cranial Nerve><Second Cranial Nerve Diseases><Structure><Testing><Therapeutic><Time><Transgenic Mice><Vacuum><Vesicle><Vitamin H><Yeasts><autophagy><axonal degeneration><axonopathy><cDNA Library><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><coenzyme R><degenerative axon><experiment><experimental research><experimental study><experiments><gene function><gene interaction><genome mutation><glaucomatous><imaging><in vivo><interventional strategy><intra-ocular pressure><mitochondrial><model of animal><mouse model><murine model><mutant><necrocytosis><neural degeneration><neural repair><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal degeneration><neuronal survival><neuroprotection><neuroprotective><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ocular hypertensive><optic nerve disorder><overexpress><overexpression><pathophysiology><pathway><receptor><retinal ganglion><second cranial nerve disorder><social role><syntaphilin><tool><trafficking><vision loss><visual loss>