Axonopathy in Glaucoma

Summary

Principal Investigator: Samuel D Crish
Abstract: DESCRIPTION (provided by applicant): Glaucoma is a chronic neurodegenerative disease that makes up one of the leading causes of blindness worldwide. Despite increasing interest, therapies that directly address the neural dysfunction and loss remain elusive. In other neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease, early pathologies occur in first in the axon - and this has been recently implicated in glaucoma. This proposal intends to examine the structural and functional defects in retinal ganglion cell axons in early glaucoma with the intention of identifying new targets for intervention in this debilitating disease. Using a combination of immunoblotting, tract tracing, histology, and quantitative immunochemistry this research enterprise will seek to determine the nature and time course of changes in cytoskeletal proteins within the axon, the enzymes responsible for these changes, and will examine different aspects of axonal transport in two rodent models of glaucoma - the DBA/2J mouse and the microbead occlusion model in rats. Specific aim 1 will examine changes in the cytoskeleton compared to two major risk factors in glaucoma: age (DBA/2J mice) and exposure to elevated intraocular pressure (Microbead Occlusion Model). Retinas, optic nerves, the superior colliculus (SC), and cerebellum (as a control structure) will be harvested and immunoblots will be performed to examine the quantity, distribution, breakdown, and phosphoisoform of four major cytoskeletal proteins and three of the most common enzymes implicated in cytoskeletal alteration in neurodegenerative disorders. Specific aim 2 will use techniques to identify cytoskeletal abnormalities in relation to neurobiological outcome measures including: 1) loss of anterograde axonal transport using intravitreal injections of the sensitive neuronal tracer cholera toxin beta subunit (CTB), and 2) axonal degeneration - immunofluorescence in the SC and optic nerve of the retinal ganglion cell (RGC) projection marker estrogen-related receptor beta (ERR[unreadable]) and the RGC terminal marker vesicular glutamate transporter 2 (VGluT2) along with axon counts in semithin sections of optic nerve. Specific aim 3 will focus on specific deficits in active axonal transport. First, the underlying causes of retrograde tracing loss in these models will be determined, i.e., to what degree it is due to functional loss of uptake/transport, blockade at the optic nerve head, axon loss, or RGC loss. This aim will use a newly-validated method of applying retrograde tracer (Fluorogold) to the SC that was developed by the principle investigator to compare degeneration measures in specific aim 1 (see above) with RGC soma in the retina. Second, we will use anterograde and retrograde tracing methods (intravitreal CTB and SC-applied fluorogold) in the same animals to determine temporal differences in defects in anterograde vs. retrograde transport that have been suggested by the glaucoma literature, yet never directly tested. This proposal is designed with the goal of identifying new therapeutic targets for this disease as well as identifying the potential role that function-restoring therapies could play in glaucoma and other neurodegenerative diseases.
Funding Period: 2012-05-01 - 2017-04-30
more information: NIH RePORT

Research Grants

  1. Role of endothelin receptors in glaucomatous optic neuropathy
    Raghu R Krishnamoorthy; Fiscal Year: 2013
  2. Optic Nerve Aging and Glaucoma
    Thasarat Vajaranant; Fiscal Year: 2013
  3. Jules Stein Eye Institute Core Grant for Vision Research
    Wayne L Hubbell; Fiscal Year: 2013
  4. Interleukin-6 and Retinal Ganglion Cell Degeneration in Glaucoma
    Rebecca M Sappington; Fiscal Year: 2013
  5. Understanding neuronal and axonal degeneration in a murine model of human MS
    Shu Wei Sun; Fiscal Year: 2013
  6. New Approaches to Dementia Heterogeneity
    Bruce L Miller; Fiscal Year: 2013
  7. Mayo Alzheimer's Disease Research Center
    Ronald C Petersen; Fiscal Year: 2013
  8. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Role of endothelin receptors in glaucomatous optic neuropathy
    Raghu R Krishnamoorthy; Fiscal Year: 2013
    ..The information gained from this study could be useful in developing endothelin receptor antagonists as neuroprotective agents in glaucoma treatment. ..
  2. Optic Nerve Aging and Glaucoma
    Thasarat Vajaranant; Fiscal Year: 2013
    ..More broadly, this work serves as a foundation for a future line of investigations into sex-differences and non-hormonal mechanisms of optic nerve aging and risks for glaucoma. ..
  3. Jules Stein Eye Institute Core Grant for Vision Research
    Wayne L Hubbell; Fiscal Year: 2013
    ..Support in the form of the Core grant is requested to maintain these Modules through instrument service contracts, and to provide necessary personnel support to assist and train users and provide routine maintenance. ..
  4. Interleukin-6 and Retinal Ganglion Cell Degeneration in Glaucoma
    Rebecca M Sappington; Fiscal Year: 2013
    ..We propose a series of studies to examine the potential of the inflammatory cytokine interleukin-6 as a therapeutic target to rescue RGCs in glaucoma. ..
  5. Understanding neuronal and axonal degeneration in a murine model of human MS
    Shu Wei Sun; Fiscal Year: 2013
    ..The findings of this study will provide significant clinical relevance as to move therapeutic strategies toward a better efficient and direct treatment to prevent permanent disability for Multiple Sclerosis. ..
  6. New Approaches to Dementia Heterogeneity
    Bruce L Miller; Fiscal Year: 2013
    ..Finally, we will create ideal data management approaches for neurodegenerative conditions that will be shared with other ADRCs, beginning with UC-Davis. ..
  7. Mayo Alzheimer's Disease Research Center
    Ronald C Petersen; Fiscal Year: 2013
    ..The ADRC will also continue to be a training platform for young investigators. ..
  8. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..