Glaucoma is an age-related neurodegenerative disease that causes blindness due to selective deterioration and death of retinal ganglion cells (RGCs). While multiple risk factors, including elevated intraocular pressure (IOP) can contribute to glaucoma, the molecular and cellular mechanisms responsible for RGC degeneration are not known. Microglia have been implicated in multiple neurodegenerative diseases, including human glaucoma as well as various animal models of the disease. Here we investigate the fractalkine signaling pathway since it regulates communication between neurons and microglia in the CNS. We propose that disruption of this pathway contributes to enhanced microglia activation and increased degeneration of RGCs in glaucoma. Using two different animal models of glaucoma, we will first test whether disruption of fractalkine signaling increases microglia activation and/or RGC degeneration. Next, we will use adeno-associated viral delivery to increase fractalkine expression and test whether this limits microglia activation and/or is reduces RGC degeneration. Finally, to elucidate the molecular signature of microglia responses in glaucoma, we will generate a comprehensive molecular profile of microglia activation, and regulation by fractalkine signaling. The findings from this work will provide significant insight ito the molecular pathways involved in glaucomatous pathology, and advance efforts to develop therapeutic interventions for slowing or preventing vision loss in glaucoma.

Public Health Relevance

Glaucoma causes blindness due to the progressive degeneration of retinal ganglion cells. Microglia are resident immune cells that have emerged as critical players in disease progression, but the mechanisms regulating their activity in the eye are poorly understood. To facilitate the development of new treatments for the disease we are testing pathways that may constrain the activity of microglia in glaucoma and potentially slow or halt vision loss.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023621-02
Application #
8712498
Study Section
(DPVS)
Program Officer
Chin, Hemin R
Project Start
2013-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Biology
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Bosco, Alejandra; Breen, Kevin T; Anderson, Sarah R et al. (2016) Glial coverage in the optic nerve expands in proportion to optic axon loss in chronic mouse glaucoma. Exp Eye Res 150:34-43
Bosco, Alejandra; Romero, Cesar O; Ambati, Balamurali K et al. (2015) In vivo dynamics of retinal microglial activation during neurodegeneration: confocal ophthalmoscopic imaging and cell morphometry in mouse glaucoma. J Vis Exp :e52731
Bosco, Alejandra; Romero, Cesar O; Breen, Kevin T et al. (2015) Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma. Dis Model Mech 8:443-55