Molecular Analysis of Retinal Ganglion Cell Death

Project: Research project

Project Details

Description

DESCRIPTION (From the Applicant's Abstract): Retinal ganglion cell death is the
final common pathway of almost all diseases of the optic nerve including
glaucoma. Glaucoma is a leading cause of blindness and, although a number of
risk factors have been identified, its causes remain unclear. Excitotoxins may
be a major cause of cell death in glaucoma and the overall goal of this project
is to determine the molecular mechanisms by which a variety of excitotoxic
agents induce ganglion cell apoptosis. The proposal has four specific aims. In
the first aim the hypothesis that glutamate induces apoptosis through a
caspase-9 mediated pathway will be tested. In addition, other factors,
including ischemia will be tested to determine whether they can act
synergistically to exacerbate the effects of low concentrations of
excitotoxins. In the second specific aim the hypothesis that mitochondrial
uncoupling proteins can reduce excitotoxic ganglion cell death will be tested.
The sensitivity of ganglion cells to excitotoxic and ischemic insults will be
tested in culture and in the intact eye using genetically engineered mouse
strains that overexpress or under express the protein UCP2. The third aim will
test the hypothesis that functional disorders of Muller glial cells may
contribute to excitotoxic ganglion cell death. In particular, a variety of
agents will be tested for their ability to inhibit Muller cell glutamate
uptake. The final aim will test the hypothesis that direct cell contact can
protect ganglion cells from the toxic effects of nitric oxide. The specificity
of this effect will be tested with a variety of cell types and the need for
membrane contact by living cells will be tested using a variety of biochemical
fractions. Overall, the experiments in this proposal will shed light on
mechanisms of cell death of particular relevance to glaucoma. They will also
further elucidate mechanisms of interaction between retinal ganglion cells and
Muller glial cells. By identifying molecules that can alter responses to
excitotoxins or ischemia, this proposal is likely to provide potential targets
for novel therapeutic interventions to prevent or slow the progression of
blindness resulting from glaucoma.
StatusFinished
Effective start/end date2/1/021/31/03

Funding

  • National Eye Institute: $367,875.00

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