Wednesday, April 2, 2025
4/2/2025
PERK dependent mechanisms of neuroinflammation - Abstract: Ischemic stroke affects a substantial number of people leading to long-term disability or death. Despite the prevalence of stroke, few treatment options are available. During an ischemic stroke, blood flow to a region of the brain is restricted preventing delivery of oxygen and essential nutrients. This leads to a complex environment within and around the infarcted tissue. This includes rapid cell death, inflammation, and endoplasmic reticulum (ER) stress in the surviving cells. The impact of ER stress on astrocytes and microglia and the resulting functional outcomes are unknown. ER stress activates the serine/threonine kinase protein kinase R-like ER kinase (PERK) which phosphorylates the eukaryotic initiation factor 2α (eIF2α) to attenuate protein translation. Our previous work has shown that PERK also activates the tyrosine kinase Janus kinase 1 (JAK1) to drive inflammatory gene expression. Additionally, our preliminary data show that PERK-dependent attenuation of protein translation enhances cytokine-induced inflammation in astrocytes and enhances neuronal death. Based on these findings, we hypothesize that PERK and JAK1 signaling contribute to worse stroke outcome and that targeting translational repression may provide therapeutic benefit. In this cycle, we will test this directly by deleting PERK in astrocytes and microglia to examine how PERK contributes to outcome in the stroke model of middle cerebral artery occlusion (MCAO). We will examine how translational suppression and JAK1 contribute to neuronal death and inflammation. Additionally, we will use the small molecule ISRIB to restore protein translation following MCAO to examine effects on functional outcome. We anticipate that deletion of PERK or restoration of protein translation will improve outcome following MCAO. Thus, identifying this signaling axis as a potential therapeutic target and furthering our understanding of glial biology.
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