Summary: Retinal detachment (RD), caused by injury or retinal disorders (e.g. age-related macular degeneration and diabetic retinopathy), is a leading cause of retinal degeneration and vision loss. In patients with sustained RD, progressive visual decline due to photoreceptor cell death is common and leads to a significant decrease in visual acuity. However, the underlying biological processes controlling photoreceptor cell death in this context are not well understood and currently no treatments exist, aside from surgery to reattach the retina. Cell death during RD is thought to be caused by the physical separation between the photoreceptors and their primary source of oxygen and nutrients resulting in severe ischemia and metabolic distress. Our preliminary evidence has demonstrated that male mice with a RD have a significant increase in photoreceptor cell death compared to their female counterparts. Moreover, we have identified estrogen as a key modulator of photoreceptor susceptibility to RD injury. Importantly, in many brain degenerative diseases, estrogen exerts its neuroprotective actions by improving mitochondrial function and reducing oxidative damage. The goal of this study therefore is to test the hypothesis that females are protected from RD-induced retinal degeneration through the actions of estrogen-dependent normalization and/or rescue of photoreceptor metabolic dysfunction. We will utilize a well-defined mouse model of RD, in which a subretinal injection of sodium hyaluronate is used to create a detachment. The mouse RD model will allow us to take advantage of well-established genetic manipulation platforms in mice in a controlled setting. In order to characterize the role of sex and the estrogen signaling system in photoreceptor cell death we will: 1) Define how estrogen signaling is modulated in vivo using genetic models and gonadectomy to precisely delineate the signaling pathways and metabolic processes involved in estrogen-dependent rescue of photoreceptor degeneration; 2) Elucidate the role of estrogen in alleviating mitochondrial stress and oxidative damage in photoreceptors in response to RD; 3) Delineate the specific metabolic pathways, key metabolites and mitochondrial functions involved in the sex dependent regulation of cell death in RD. It is our belief that this study will yield insights into the role of estrogen in retinal neuroprotection and provide new sex-specific therapeutic targets and or treatment modalities for the management of sight-threatening diseases such as RD.