Transcriptional control of NK cell metabolism

NK细胞代谢的转录控制

• 批准号: 10219883
• 负责人: Joseph Chai-Yuen Sun
• 金额: $ 77.62万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219883
• 关键词: ATAC-seq; Ablation; Activated Natural Killer Cell; Antiviral Agents; Antiviral Response; Binding; Biological Assay; Biology; Cancer Patient; Carnitine Palmitoyltransferase I; Cell Compartmentation; Cells; Cellular Metabolic Process; ChIP-seq; Chemicals; Chromatin; Clonal Expansion; Communicable Diseases; Competence; Complement; Critical Pathways; Cytomegalovirus; Cytomegalovirus Infections; Data; Data Analyses; Deposition; Disease; Engineering; Enzymes; Epigenetic Process; Exhibits; Exposure to; Family; Fatty Acids; Flow Cytometry; Generations; Genes; Genetic Transcription; Genus Hippocampus; Glycolysis; Goals; Grant; Health; Histones; Host Defense; Human; Immune; Immunity; Immunization; Immunologic Memory; In Vitro; Individual; Infection; Innate Immune System; Laboratories; Lead; Life; Lymphocyte; Mass Spectrum Analysis; Measures; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Murid herpesvirus 1; Mus; NK Cell Activation; Natural Killer Cells; Newborn Infant; Oxygen Consumption; Pathway interactions; Patients; Play; Predisposition; Promoter Regions; RNA; Regulation; Reporter; Research; Rest; Role; STAT4 gene; Therapeutic; Transcriptional Regulation; Transgenic Mice; Transplant Recipients; Up-Regulation; Viral; Virus; Virus Diseases; aerobic glycolysis; arm; base; cytokine; epigenomics; experimental study; extracellular; fatty acid oxidation; fighting; immunosuppressed; in vivo; inhibitor/antagonist; lactate dehydrogenase A; metabolic abnormality assessment; metabolomics; mitochondrial fitness; mitochondrial metabolism; mouse model; novel; oxidation; pathogen; response; transcription factor; transcriptome sequencing; transcriptomics

Project Summary Natural killer (NK) cells comprise an important arm of the host innate immune system that detects and eliminates virus-infected cells. Newborns and immune-compromised patients lacking NK cells are extremely susceptible to viral infection. In particular, human cytomegalovirus (HCMV) can cause severe health complications or be life-threatening in these individuals. Mouse cytomegalovirus (MCMV) is an accurate and robust model for investigating NK cell responses against HCMV. Using MCMV infection in mice, we have discovered that NK cells possess novel adaptive immune features such as clonal expansion and long-lived memory. In the past decade, our laboratory has uncovered many of the cellular and molecular mechanisms underlying NK cell memory. Our long-term goals are to understand the general biology of NK cells, and the molecular basis by which these powerful innate lymphocytes can mediate protection against pathogen invasion. To this end, we have recently identified several transcriptional and metabolic pathways that may influence the NK cell response against MCMV infection. Based on this exciting preliminary data, our current R01 grant proposes to use cutting edge metabolomics and newly engineered transgenic mouse models to study how metabolism in antiviral NK cells in transcriptionally regulated. In Aim 1, we seek to understand how proinflammatory cytokines and the STAT family of transcription factors control of NK cell metabolism during MCMV infection. In Aim 2, we will determine the requirement for aerobic glycolysis and fatty acid oxidation in antiviral NK cells using conditional ablation of genes encoding LDHA and CPT1a, respectively. In Aim 3, we will determine whether the transcription factor Bhlhe40 regulates mitochondrial metabolism and fitness in effector NK cells fighting MCMV infection. Altogether, the studies in this R01 proposal will greatly increase our understanding of the underlying transcriptional and metabolic mechanisms whereby NK cells contribute to host defense during viral infection, and establish novel translational paradigms for harnessing the NK cell compartment for immunization and therapeutic strategies against infectious diseases.

项目概要 自然杀伤 (NK) 细胞是宿主先天免疫系统的重要组成部分，负责检测和 消除病毒感染的细胞。缺乏 NK 细胞的新生儿和免疫功能低下的患者 极易受到病毒感染。特别是，人类巨细胞病毒（HCMV）可导致严重的 这些人会出现健康并发症或危及生命。小鼠巨细胞病毒（MCMV）是一种 用于研究 NK 细胞对 HCMV 反应的准确而稳健的模型。使用 MCMV 感染 在小鼠中，我们发现 NK 细胞具有新的适应性免疫特征，例如克隆性 扩展和长期记忆。在过去的十年中，我们的实验室发现了许多细胞 以及 NK 细胞记忆的分子机制。我们的长期目标是了解 NK 细胞的一般生物学，以及这些强大的先天淋巴细胞能够发挥作用的分子基础 介导针对病原体入侵的保护。为此，我们最近确定了一些 可能影响 NK 细胞对 MCMV 感染反应的转录和代谢途径。 基于这些令人兴奋的初步数据，我们当前的 R01 拨款建议使用尖端代谢组学 以及新设计的转基因小鼠模型来研究抗病毒 NK 细胞的代谢 转录调控。在目标 1 中，我们试图了解促炎细胞因子和 STAT 如何 MCMV 感染期间控制 NK 细胞代谢的转录因子家族。在目标 2 中，我们将 使用以下方法确定抗病毒 NK 细胞中有氧糖酵解和脂肪酸氧化的需求 分别编码 LDHA 和 CPT1a 的基因的条件消融。在目标 3 中，我们将确定 转录因子 Bhlhe40 是否调节效应子 NK 中的线粒体代谢和适应性 细胞对抗 MCMV 感染。总而言之，本 R01 提案中的研究将大大增加我们的 了解 NK 细胞贡献的潜在转录和代谢机制 在病毒感染期间宿主防御，并建立利用 NK 的新翻译范例 用于针对传染病的免疫和治疗策略的细胞室。