Manipulation of metabolic pathways to enhance human macrophage phenotypes after ICH

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Project Summary. Intracerebral hemorrhage (ICH) is a devastating stroke subtype with high mortality and morbidity and no effective treatment. We have shown in murine models of ICH that blood-derived macrophages initially contribute to injury but over time are crucial to the resolution of inflammation and brain repair. This work highlights the modulation of macrophage phenotype as an important potential therapeutic strategy. Emerging data in murine cells has revealed that cellular metabolism is fundamentally linked to the inflammatory response of the cell. However, studies on these mechanisms in human cells have been limited and the findings have not been studied in the context of a complex neurological injury such as ICH. Determining whether the pathways seen in rodents are relevant in patients is critical to the successful development of new therapies for the treatment of ICH. The overall goal of this proposal is to determine whether macrophage metabolism can be manipulated to reduce proinflammatory cytokine production and enhance erthyrophagocytosis and growth factor production. These functions of macrophages are critical to injury and recovery after ICH. In the proposed experiments, we will (1) determine the effects of macrophage metabolic pathways on inflammatory and reparative phenotypes in human cells after ICH-relevant stimuli, (2) determine the effects of important biological variables on the manipulation of metabolic pathways in human macrophages, and (3) investigate whether pharmacological manipulation of macrophage metabolism can modulate the inflammatory response in vivo in murine experimental ICH.