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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.

项目总结