Axonal cytoskeletal changes in experimental glaucoma

Legacy Emanuel Hospital And Health Center, Portland OR

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Abstract

DESCRIPTION (provided by applicant): Evidence we and others have published unequivocally demonstrates that retinal nerve fiber layer (RNFL) retardance measured by scanning laser polarimetry (SLP) declines prior to and faster than RNFL thickness measured by optical coherence tomography (OCT) following experimental retinal ganglion cell (RGC) axonal injury, including non-human primate (NHP) unilateral experimental glaucoma (EG). SLP detects the relative degree of phase retardance manifest by a scanning beam after it passes through the birefringent RNFL tissue. Normal RNFL tissue inherently exhibits strong birefringence primarily because its axons are enriched with a dense, orderly array of axonal cytoskeletal elements, microtubules in particular. SLP measurements of RNFL retardance thus provide a clinical assay of RNFL axonal cytoskeletal integrity. We have shown that these early RNFL retardance abnormalities are accompanied by loss of RGC function and that by the time RNFL thickness changes are detected by spectral domain OCT (SDOCT), 10-15% of the orbital optic nerve axons are lost. The current proposal will extend this line of investigation in two ways that are critical to translating our findings to the clinical management of human glaucoma patients. First, we will test the hypothesis that early-stage RNFL retardance abnormalities are associated with axonal transport deficits. Second, we will test the hypothesis that early RNFL retardance abnormalities are reversible by lowering intraocular pressure (IOP), that reversal is enhanced by calcium channel regulation, and that reversal will be protective against subsequent RGC functional loss, RNFL thinning, axonal transport disruption and optic nerve axon loss. The Specific Aims of the project are: Specific Aim 1: To test the prediction that sectoral abnormalitie of RNFL retardance (measured by SLP) are predictive of subsequent sectoral RNFL thinning (measured by SDOCT) and of subsequent sectoral retinal dysfunction (measured by multifocal electroretinography). Specific Aim 2: To test the hypothesis that axonal transport deficits exist a the onset of RNFL retardance changes measured by SLP. Specific Aim 3: To test the hypothesis that RNFL retardance changes measured by SLP are reversible upon topical therapeutic intervention and that reversal will be protective against subsequent progressive RGC functional loss and RNFL thinning measured in vivo, as well as axonal transport disruption and optic nerve axon loss (assessed by post mortem histopathological studies). Proving that early-stage RNFL retardance abnormalities are associated with axonal transport disruption and that their reversal by common topical therapeutic intervention is protective against subsequent progressive RGC functional changes and optic nerve axon loss will have direct, translational relevance to the clinical care of human glaucoma patients and provide insight into the pathophysiological sequence of glaucomatous axonal degeneration.