PROJECT SUMMARY There is growing evidence that some diseases can be influenced by biological sex, where male or female patients have worsened outcomes or faster disease progression. However, the molecular mechanisms underlying the interaction of systemic sex hormones and disease are largely unknown. There is a critical need to understand the molecular basis of how circulating sex hormones can impact disease progression. I have shown that a mouse model of rhodopsin P23H Retinitis Pigmentosa (RP) presents as sexually dimorphic, where disease progression is increased in females compared to males. RP is a group of devastating visual disorders that cause the death of the photoreceptor neurons, leading to blindness. In addition to my findings of sexual dimorphism in retinal disease progression in RP, I have discovered that this sex difference can be ameliorated by depletion of estrogen and progesterone. Re-introduction of either of these sex hormones can worsen visual decline. The overall goal of my work is to understand the mechanisms that influence photoreceptor cell death in RP. Specifically, this proposal aims to determine how systemic sex hormones impact cell death and stress responses in the rhodopsin (Rho) P23H form of RP. To do so, I will first employ targeted molecular biology techniques to analyze the effect of circulating estrogen and progesterone on the unfolded protein response and caspase- mediated cell death. By investigating these two pathways, I will describe how the hormones that are detrimental to photoreceptor health in RP are affecting two of the central molecular mechanisms underlying this disease. Next, I will investigate how these hormones are able to carry out their detrimental functions by defining the hormone receptors that mediate this response through in vivo antagonist/ agonist studies. Furthermore, I will determine the genetic control of the hormone signaling in the retina through RNA sequencing. Together, these aims will inform how and what is being altered in the Rho P23H retina in response to hormone signaling. Successful completion of this project will be vital for informing the clinical safety of hormonal medications for patients with this form of RP, as well as discovering new pathways that can affect photoreceptor degeneration. Furthermore, this work provides me the opportunity to advance my skills in the study of hormone signaling and cellular stress and promotes my career goals of becoming an independent investigator.