Transcriptional control of NK cell metabolism

NK细胞代谢的转录控制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要天然杀手（NK）细胞包括宿主先天免疫系统的重要部门，该系统检测和消除感染病毒的细胞。缺乏NK细胞的新生儿和免疫功能低下的患者是极易受到病毒感染的影响。特别是，人类巨细胞病毒（HCMV）可能引起严重健康并发症或在这些人中威胁生命。小鼠巨细胞病毒（MCMV）是用于研究针对HCMV的NK细胞反应的准确模型。使用MCMV感染小鼠，我们发现NK细胞具有新颖的自适应免疫特征，例如克隆扩展和长寿记忆。在过去的十年中，我们的实验室发现了许多细胞 NK细胞记忆的基础机制和分子机制。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可以通过的分子基础介导防止病原体入侵的保护。为此，我们最近确定了几个转录和代谢途径可能影响NK细胞反应针对MCMV感染。基于这个令人兴奋的初步数据，我们当前的R01赠款建议使用前沿代谢组学以及新设计的转基因小鼠模型，以研究抗病毒NK细胞中的代谢如何转录调节。在AIM 1中，我们试图了解促炎性细胞因子和统计转录因子家族在MCMV感染过程中控制NK细胞代谢。在AIM 2中，我们将使用使用抗病毒NK细胞中有氧糖酵解和脂肪酸氧化的需求编码LDHA和CPT1A的基因的条件消融。在AIM 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与MCMV感染作斗争的细胞。总之，这项R01提案中的研究将大大增加我们的了解基本的转录和代谢机制，NK细胞有助于在病毒感染期间举办防御，并建立新的翻译范例来利用NK 针对传染病的免疫和治疗策略的细胞室。