Manipulation of metabolic pathways to enhance human macrophage phenotypes after ICH

项目摘要。 脑出血(ICH)是一种严重的卒中亚型，具有较高的死亡率和致残率。 有效的治疗。我们已经在脑出血的小鼠模型中表明，最初血液来源的巨噬细胞 会导致损伤，但随着时间的推移，对炎症的消退和大脑修复至关重要。这部作品 强调巨噬细胞表型的调节是一种重要的潜在治疗策略。新兴 小鼠细胞中的数据显示，细胞新陈代谢从根本上与炎症反应有关 在牢房里。然而，对人类细胞中这些机制的研究一直是有限的，而且研究结果还没有 在脑出血等复杂神经损伤的背景下进行了研究。确定这些路径是否 在啮齿动物身上看到的与患者相关的是成功开发新的治疗方法的关键 脑出血的治疗。 这项提议的总体目标是确定巨噬细胞的代谢是否可以被操纵来 减少促炎细胞因子的产生，增强甲状腺吞噬功能和生长因子的产生。 巨噬细胞的这些功能对脑出血后的损伤和恢复至关重要。在建议的实验中，我们 将(1)确定巨噬细胞代谢途径对炎症和修复表型的影响 人类细胞在脑出血相关刺激后，(2)确定重要的生物变量对 人巨噬细胞代谢途径的调控，以及(3)研究药理作用是否 巨噬细胞代谢调控对体内炎症反应的调节作用 实验性脑出血。

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.