METABOLIC REGULATION OF NATURAL KILLER CELL ACTIVATION

自然杀伤细胞激活的代谢调节

• 批准号: 9914085
• 负责人: MEGAN Anne COOPER
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914085
• 关键词: Affect; Antiviral Agents; Binding; Cell Count; Cell Differentiation process; Cell physiology; Cells; Data; Defect; Disease; Drug Targeting; Effector Cell; Elements; Fatty Acids; GTP-Binding Proteins; Generations; Genetic Transcription; Glucose; Glycolysis; Glycolysis Inhibition; Goals; Health; IFNG gene; ITAM; Immune; Immunity; Immunologic Surveillance; Immunotherapy; Impairment; Infection; Infection Control; Inflammatory; Interferon Type II; Interleukin-15; Knowledge; Laboratories; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; Memory; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Murid herpesvirus 1; Mus; NK Cell Activation; Natural Killer Cells; Oxidative Phosphorylation; Pathway interactions; Patients; Play; Production; Receptor Activation; Recurrence; Regulation; Ribosomes; Role; Signal Transduction; T memory cell; Transcript; Translations; Virus; Virus Diseases; antitumor effect; cell killing; cytokine; drug candidate; human disease; improved; in vivo; inhibitor/antagonist; insight; interest; mortality; mouse model; neoplastic cell; pathogen; preservation; receptor; response; transcription factor; tumor

PROJECT SUMMARY The long-term goal of this project is to determine the metabolic regulation of NK cell effector functions to improve our understanding of basic mechanisms of NK cell activation in health and disease. Natural killer (NK) cells are innate immune lymphocytes that serve as a critical first line defense against infection, particularly viruses, and are important for tumor immunosurveillance. NK cells mediate their effects via two mechanisms: production of cytokines (especially IFN-gamma) and target cell killing. NK cell effector functions can be triggered by inflammatory cytokines or engagement of germline-encoded activating receptors whose ligands are displayed by infected and/or tumor cells. Metabolic regulation plays a key role in many aspects of immunity, including the activation and generation of memory T cells. There are two primary metabolic pathways for generating intracellular energy (ATP), glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). The fuels that drive cellular metabolism (e.g., glucose, fatty acids) are altered in many disease states, and metabolic pathways are promising targets for drug candidates. While triggers of NK cell activation and subsequent NK cell effector responses have been well-characterized, the metabolic fuels required for NK cell functional responses, and the concept of metabolic regulation of NK cell activation are largely unexplored. Our preliminary data demonstrates that both OXPHOS and glycolysis are required for activation of NK cells by activating receptors, but that cytokine stimulation of NK cells does not require a specific metabolic pathway. Following priming with IL-15, the metabolic requirements for NK cell activation are altered, and NK cells have preserved function in response to receptor activation with metabolic inhibition. This proposal presents a 5 year plan to investigate the metabolic regulation of NK cell activation. We hypothesize that alterations of intrinsic cellular metabolism will impact NK cell function in vivo. The specific aims of this proposal are to investigate: 1) the mechanisms by which receptor stimulation of NK cells is dependent on metabolism and how IL-15 priming alters this, and 2) the metabolic requirements for NK cell differentiation and response to viral infection in vivo using genetically targeted mouse models. These studies will provide insight into metabolic pathways that control NK cell activation, and potential pathways to target in patients to enhance NK cell function.

项目总结 该项目的长期目标是确定NK细胞效应器功能的代谢调节，以 提高我们对健康和疾病中NK细胞激活的基本机制的理解。自然杀手(NK) 细胞是先天免疫淋巴细胞，是抵御感染的关键第一道防线，尤其是 病毒，并对肿瘤免疫监控很重要。NK细胞通过两种机制调节它们的作用： 产生细胞因子(尤其是干扰素-γ)和靶细胞杀伤。NK细胞效应器功能可以 由炎性细胞因子或其配体为生殖线编码的激活受体的参与而触发 由感染的和/或肿瘤细胞表现出来。代谢调节在许多方面起着关键作用 免疫，包括记忆T细胞的激活和生成。有两种主要新陈代谢 细胞内能量产生途径(ATP)、糖酵解和线粒体氧化磷酸化 (OXPHOS)。驱动细胞新陈代谢的燃料(如葡萄糖、脂肪酸)在许多疾病中都会发生变化 新陈代谢途径是候选药物的有希望的目标。而NK细胞激活的触发物 随后的NK细胞效应反应已经被很好地描述，NK所需的代谢燃料 细胞功能反应和NK细胞激活的代谢调节的概念在很大程度上是未知的。 我们的初步数据表明，OXPHOS和糖酵解都是激活NK细胞所必需的 激活受体，但细胞因子对NK细胞的刺激不需要特定的代谢途径。 在IL-15启动后，NK细胞激活的代谢需求发生改变，NK细胞 在代谢抑制的情况下，对受体的激活做出反应而保留的功能。这份建议书的期限是5年。 目的：探讨NK细胞活化的代谢调控。我们假设内在的变化 体内的细胞代谢会影响NK细胞的功能。这项提案的具体目的是调查：1) NK细胞受体刺激依赖代谢的机制及IL-15如何启动 改变这一点，以及2)体内NK细胞分化和对病毒感染的反应的代谢要求 使用基因定位的小鼠模型。这些研究将提供对代谢途径的洞察 控制NK细胞的激活，并通过潜在的靶向途径来增强患者的NK细胞功能。