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 into the molecular pathways involved in glaucomatous pathology, and advance efforts to develop therapeutic interventions for slowing or preventing vision loss in glaucoma. !
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.
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|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|