Microglial Activation during Photoreceptor Degeneration

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Project Summary Retinal degeneration is a leading cause of blindness worldwide. All current treatments for retinal degeneration, including experimental therapeutics like stem cell or gene replacement therapy, are thought to be most effective when degeneration is caught in its earliest stages. Unfortunately, the earliest detectable symptom of degeneration is often visual impairment, which is only detectable after a large number of retinal cells have died and disappeared. The ability to discern the first signs of cell stress, prior to apoptosis and degeneration, could significantly improve the likelihood of delaying or preventing vision loss. One common early indication of degeneration is activation of an immune response, as the resident macrophages, called microglia, and infiltrating monocytes migrate to and phagocytose injured neurons. The proposed research will utilize high- resolution, in vivo OCT and AO-SLO imaging, flow cytometry, scRNAseq and biochemical and immunohistochemical approaches to study the microglial response to photoreceptor degeneration (Aim 1), the fates of infiltrating monocytes (Aim 2), and the involvement of both cell types in re-establishing new homeostasis after dying photoreceptors have been cleared (Aim 3). This work will contribute to the long-term goal of monitoring and manipulating microglial dynamics in vivo so as to provide earlier detection of and assessment of treatments for retinal degenerative disease.