Role of Soluble Adenylate Cyclase in Reactive Astrocytes

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): Central nervous system (CNS) injury and/or degeneration triggers numerous changes in gene expression, signaling and cellular interactions that result in permanent changes in tissue architecture and CNS function. Astrocytes respond to injury in a process referred to as reactive astrogliosis that includes both beneficial and ultimatey harmful functions. Cyclic-AMP (cAMP) has been demonstrated to play a significant role in regulating astrocyte physiology both during development and in response to injury. Recently, soluble adenylyl cyclase (sAC), a unique bicarbonate- and calcium-activated source of cAMP, was shown to play a role in retinal ganglion cell (RGC) survival and axon growth. In astrocytes, sAC-mediated signaling underlies a major metabolic pathway that provides energy to neurons during ischemic-like conditions. Our and others' data suggest that sAC signaling in astrocytes is necessary for retinal ganglion cell (RGC) survival and perhaps for regeneration after optic nerve injury. Based on our preliminary data, I hypothesize that astrocyte sAC is required for RGC survival and neurite patterning during development, and that sAC activity in astrocytes promotes RGCs survival and regeneration after optic nerve injury. To address this hypothesis, I will determine the levels of sAC expression in astrocytes during development and after ONC injury by immunofluorescence. To investigate astrocyte sAC in retinal development and reactive astrogliosis, I will use a floxed sAC allele to conditionally knock-out sAC in astrocytes at differnt developmental time points and after optic nerve injury to specifically measure the effect of astrocyte sAC on RGCs. The overall goal of this study is to better understand how astrocyte sAC influences reactive astrogliosis and neuronal survival and regeneration, highlighting it as a potential therapeutic target.