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Manipulation of metabolic pathways to enhance human macrophage phenotypes after ICH

控制代谢途径以增强 ICH 后的人类巨噬细胞表型

基本信息

批准号：
10308104
负责人：
LAUREN H SANSING
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308104
关键词：
Acute Age Amino Acids Anti-Inflammatory Agents Ants Arteries Biological Blood Bone Marrow Brain Brain Injuries Cell Proliferation Cell model Cells Cerebral hemisphere hemorrhage Chemotaxis Chimera organism Complex Coupling Data Deoxyglucose Development Disease Erythrocytes Erythrophagocytosis Experimental Models Gene Expression Generations Glucose Glycolysis Glycolysis Inhibition Goals Growth Factor Hematoma Hemorrhage Host Defense Hour Human Hypoxia Inducible Factor Immune response In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interferon Type II Interleukin-4 Leukocytes Ligands Link Macrophage Activation Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolism Modeling Morbidity - disease rate Mus Nervous System Physiology Nervous System Trauma Neurologic Nucleic Acids Outcome Oxidative Phosphorylation Oxygen Pathway interactions Patient-Focused Outcomes Patients Phagocytosis Pharmacology Phase Phenotype Production Reaction Resolution Rodent Role Rupture S100A9 gene Signal Transduction Sterility Stimulus Stroke Testing Therapeutic Time Tissues Toll-like receptors Warburg Effect Work age effect brain parenchyma brain repair cell growth cytokine disability effective therapy experimental study fatty acid oxidation functional outcomes improved in vitro Assay in vivo injury recovery macrophage monocyte mortality mouse model neurological recovery novel therapeutics pathogen recruit repair function response sex targeted treatment tissue injury tumor

项目摘要

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.

项目摘要。脑出血（ICH）是一种破坏性卒中亚型，具有高死亡率和高发病率，有效治疗。我们已经在ICH小鼠模型中显示，血液来源的巨噬细胞最初有助于损伤，但随着时间的推移，对炎症的解决和大脑修复至关重要。这项工作强调了巨噬细胞表型的调节作为重要的潜在治疗策略。新兴在鼠细胞中的数据已经揭示了细胞代谢与炎症反应基本上相关的细胞。然而，在人类细胞中对这些机制的研究是有限的，这些发现并没有在复杂神经损伤（如ICH）的背景下进行了研究。确定这些途径在啮齿类动物中发现的与患者相关的基因对于成功开发新的治疗方法至关重要。治疗ICH。这项提案的总体目标是确定巨噬细胞代谢是否可以被操纵，减少促炎性细胞因子的产生并增强嗜甲状腺细胞吞噬作用和生长因子的产生。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， ICH相关刺激后的人类细胞，（2）确定重要的生物学变量对操纵人巨噬细胞中的代谢途径，以及（3）研究药理学操纵巨噬细胞代谢可以调节小鼠体内的炎症反应实验性ICH。