Glaucoma is an age-related neurodegenerative disease that affects up to 60 million people worldwide. Visual field loss and blindness result from progressive deterioration of the optic axons and selective death of retinal ganglion cells (RGCs). Intraocular pressure (IOP) elevation constitutes a risk factor in glaucoma, but is not sufficient to cause disease, suggesting that other conspiring events lead to progressive decline of optic axons, loss of RGC viability and final apoptosis. The exact mechanism responsible for RGC degeneration in glaucoma is not known. In this proposal we investigate the role of microglia and complement pathways in retinal ganglion cell decline in the DBA/2J model of glaucoma. Microglia, the resident immune surveillance cells of the CNS, are exquisitely sensitive to neuronal stress and injury, and have been implicated in multiple neurodegenerative diseases. There is evidence that microglia become activated in human glaucoma as well as in various animal models, however the consequences of microglial activation in glaucoma remains unknown. In this proposal we will document the relationship between microglia activation and RGC decline. We will then inducibly deplete microglia from the retina, or inhibit complement pathways in the retina, and assess the effects on RGC degeneration. This study will provide the first detailed investigation of the functional consequences of microglia activation and complement expression in an animal model of glaucoma. The findings from this work may form the basis for testing therapeutic interventions targeting microglia or complement pathways in human glaucoma.

Public Health Relevance

Glaucoma is a devastating neurodegenerative disease of the eye, and is a leading cause of blindness worldwide. The cellular and molecular players involved in disease progression are only partially understood, limiting the ability to develop new innovative treatments for the disease. The experiments in this proposal will extend the knowledge about the role of microglia and innate immunity pathways in glaucoma. This may reveal potential candidate biomarkers for the disease as well as novel targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY020878-03
Application #
8317675
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$322,920
Indirect Cost
$106,920
Name
University of Utah
Department
Biology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112