ABSTRACT Retinal diseases are a leading cause of blindness, tremendously impacting patients and society. A root cause of poor vision is death of the photoreceptor cell, which primarily results from disruption of the normal homeostatic interaction between these cells and the underlying retinal pigment epithelium (RPE). Preserving photoreceptor (PR) viability and function remains a critical unmet medical need. PRs have the highest oxygen consumption in the body. The choroidal vasculature supplies this demand through the RPE – a process that requires close apposition and intimate interaction. Periods of disrupted retina-RPE homeostasis might be expected to result in marked and rapid PR cell death. However, PRs can survive periods of reduced RPE nutritional support, resulting in a clinical window of opportunity for treating retinal disease. Currently there are no therapeutic options to maintain PR viability or slow the rate of cell death to extend this treatment window. In experimental retinal detachments (RD), a validated model of altered PR-RPE homeostasis, we have found activation of both pro-survival and death pathways. Examples of the former include the release of protective cytokines and activation of autophagy; whereas cell death occurs primarily through Fas-mediated apoptosis. A major gap in our knowledge is that we do not know the upstream activators of these cytoprotective and cytodestructive pathways. We hypothesize that HMGB1 and microglia represent key intrinsic and extrinsic influences, respectively. Our preliminary data strongly point towards a role for the multifunction protein known as High-Mobility Group Box 1 (HMGB1) in the intrinsic protection of PR and the innate immune response to stressed PR. In Specific Aim 1 we will define the role of HMGB1 in PR death and activation of retinal microglia after RD and in a model of inherited retinal degeneration. Our preliminary data connects the upregulation of HMGB1 in rod PR to protective autophagy and the activation of microglia following RD. We will investigate the function of cytosolic HMGB1 in cell-autonomous activation and stabilization of pro-survival pathways within PRs and the function of released HMGB1 to promote microglial activation. In Specific Aim 2 we will determine the role of microglia in the inflammatory response and PR death following RD. The relative contributions of microglia and infiltrating myeloid leukocytes and how the immune response affects PR survival are not clear. Based on our preliminary data, we hypothesize that resident microglia are the major first responders to RD, and that microglia are initially protective but eventually shift to a detrimental inflammatory phenotype. We further hypothesize that the p38a-ULK1 axis contributes to this shift. We will define and characterize the immune cells responding to RD and test if targeting p38a and promoting autophagy are protective following RD. The work proposed in this grant will provide a critical understanding of...