Investigating multiarmed cell death (PANoptosis) in dry AMD progression

Project Summary

I hypothesize that PANoptosis, as a central unifying cell death mechanism, is the main driver of RPE degeneration in dry AMD and that it is suppressed in healthy eyes to promote survival. RPE cells are responsible for the upkeep of light-sensing photoreceptors through phagocytosis of their distal tips. I will examine changes in the PANoptosis activation status in response to this daily photoreceptor processing in homeostasis, during aging and following genetic or pharmacological inhibition of key signaling molecules in order to determine the role of PANoptosis in RPE physiology and pathology. 

While most studies to date have focused on identifying specific stress signals that lead to RPE dysfunction and with a plethora of them described to trigger seemingly distinct cell death pathways, the existence of a multiarmed cell death mechanism, such as PANoptosis, has never been considered in RPE degeneration before. My proposal directly addresses this gap in knowledge, with a hope to constitute the important first step to unraveling the complex crosstalk of signaling networks that determine RPE cell fate, to ultimately shape direction of future therapeutic strategies for dry AMD. 

Implicating PANoptosis in RPE degeneration will represent a break-through in our understanding of the complex pathological processes underlying RPE cell death and dry AMD progression. Since inhibition of such a multifaceted cell death mechanism could simultaneously block alternative arms of cell death, identifying any master regulators, that are critical for maintaining RPE functionality and promote RPE survival, will undoubtedly pave way to exploring new targets and developing novel strategies for global manipulation of cell death when therapeutically targeting RPE deterioration in dry AMD.