Cells and genes that govern inflammation in the subretinal space

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Abstract Injuries or diseases that kill retinal neurons or photoreceptors block vision at it source. The inability to repair the retina is a hallmark of the human nervous system; neurons that die are not replaced and functions that are lost are not recovered. This bleak outcome is a driving force for research on neural stem cells and the field of regeneration biology. The objective of this project is to undertake novel exploratory studies that will investigate new concepts and characterize newly-identified cell types that are hypothesized to play key roles during the death and regeneration of photoreceptors in the vertebrate retina. This work will extend projects in our lab toward new directions. This program of research utilizes the zebrafish retina, the only vertebrate CNS tissue in which endogenous cells can regenerate a single neuronal type, which integrates into existing synaptic circuits, or regenerate all cell types that can completely restore the original tissue. Two Specific Aims are proposed, each designed to reveal important insights into the cellular and molecular mechanisms that govern inflammation in subretinal space during photoreceptor death and regeneration. Specific Aim 1 will explore the role the RPE plays in establishing the inflammatory mileau within the sub-retinal space during the selective death of cone photoreceptors. Specific Aim 2 will establish the transcriptomic signature of a newly-identified population of subretinal microglia, which, like the RPE, have an exclusive relationship to photoreceptors. Determining how the inflammatory response governs photoreceptor regeneration will advance our knowledge of the molecular mechanisms that govern retinal stem and progenitor cells and may guide cell-based therapeis for treating retinal injuries and disease in humans.