Metabolic regulators of Treg/Th17 balance in CNS autoimmunity

CNS 自身免疫中 Treg/Th17 平衡的代谢调节因子

基本信息

批准号：
10708996
负责人：
VIJAY K. KUCHROO
金额：
$ 55.52万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708996
关键词：
Address Affect Algorithms Anabolism Atlases Autoimmune Autoimmune Responses Binding Binding Sites Biochemical Pathway CNS autoimmunity Cell Count Cell physiology Cells Cellular Assay Cellular Metabolic Process Cellular biology Central Nervous System Chemicals Chromatin Co-Immunoprecipitations Complex Computational algorithm Cues Cytokine Signaling DNA Binding Data Development Distant Electron Transport Elements Environment Enzymes Epigenetic Process Equilibrium Experimental Autoimmune Encephalomyelitis FOXP3 gene Generations Genes Genetic Genome Glycolysis Hypoxia Immune Inflammation Inflammatory Interleukin-10 Investigation Mediating Metabolic Metabolism Mitochondria Modification Molecular Multiple Sclerosis Mus Nuclear Ornithine Decarboxylase Outcome Oxidative Phosphorylation Oxygen Oxygen Consumption Pathogenicity Pathway interactions Phenotype Play Polyamines Post-Translational Protein Processing Process Proliferating Proteins Reaction Regulatory T-Lymphocyte Resolution Respiration Role Severities Shapes Spermidine/Spermine N1-Acetyltransferase System T cell differentiation T cell infiltration T-Cell Development T-Lymphocyte Techniques Testing Tissues autoreactivity cytokine dimer effector T cell epigenome epigenomics histone demethylase histone modification human disease in vivo inhibitor metabolic profile metabolome neuroinflammation novel programs recruit risk variant single-cell RNA sequencing tool transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ ABSTRACT Autoimmune tissue inflammation is dictated by a balance between effector and regulatory T cells. During an autoimmune reaction, effector T cells hyper proliferate, produce pro-inflammatory cytokines and suppress expansion and generation of regulatory T cells resulting in inflammation. Cytokines play a key role in the process, but other factors such as metabolism and physical factors like oxygen tension, pH and space in tissue microenvironment play an equally important role in regulating effector vs. Treg balance. However, the analysis of T cell metabolism in tissue is challenging due to limitations of available cell numbers and current metabolic techniques. We developed a novel computational algorithm called Compass that can predict metabolic state of cells using single cell RNAseq data. Facilitated by this tool, we identified polyamine metabolism as a major driver of pathogenicity of Th17 cells. Herein we observed that Odc1 inhibition can regulate mitochondrial function by increasing mitochondrial complex stability genes with potential consequences in effector T cell function. Further, our preliminary data suggests a connection between the polyamine pathway (rate limiting enzyme, Odc1) and an epigenome modifier, JMJD3/Kdm6b. We also provide evidence that inhibition of the Odc1-JMJD3 axis by chemical inhibitors or genetic deletion modifies the transcriptome and epigenome (genome accessibility) of Th17 cells in favor of Tregs with relevance in tissue inflammation in CNS in experimental autoimmune encephalomyelitis (EAE). Based on these data we hypothesize that polyamine pathway is a critical metabolic and epigenetic regulator of effector vs. Treg differentiation and thereby affects development of tissue inflammation. The key element of the pathway, Odc1- JMJD3 axis is a checkpoint that can be regulated by cytokines and can sense environmental cues such as hypoxia and subsequently adjust metabolic and epigenomic state of T cells to regulate effector vs. regulatory T cell balance. We will test this hypothesis in two aims: 1) determine how polyamine biosynthesis restricts mitochondrial oxphos and promotes reverse electron transport to impact effector vs. Treg development in inflamed CNS during EAE; 2) determine whether polyamine metabolism enzyme Odc1 interferes with JMJD3 function to modulate the genome accessibility of T cells favoring Th17 over Treg development during EAE development. The polyamine metabolism pathway likely has broader implications in T cell biology. Hence, we will focus on the relevance of the Odc1-JMJD3 axis in inflamed CNS in the context of Th17/Treg balance. The proposed study is highly relevant in human diseases as reflected by a significant overlap (about 25%) between multiple- sclerosis risk variants and genes that differentially regulate effector Th17 vs. Treg differentiation.

项目概要/摘要自身免疫组织炎症由效应 T 细胞和调节 T 细胞之间的平衡决定。在自身免疫反应期间，效应 T 细胞过度增殖，产生促炎细胞因子并抑制导致炎症的调节性 T 细胞的扩增和生成。细胞因子发挥作用在此过程中发挥关键作用，但其他因素如新陈代谢和身体因素如氧张力，组织微环境中的 pH 值和空间在调节效应子和 Treg 方面发挥着同样重要的作用平衡。然而，由于以下因素的限制，组织中 T 细胞代谢的分析具有挑战性：可用的细胞数量和当前的代谢技术。我们开发了一种新颖的计算称为 Compass 的算法可以使用单细胞 RNAseq 数据预测细胞的代谢状态。借助该工具，我们确定多胺代谢是 Th17 致病性的主要驱动因素细胞。在此，我们观察到 Odc1 抑制可以通过增加线粒体功能来调节线粒体功能。线粒体复合体稳定性基因对效应 T 细胞功能具有潜在影响。更远，我们的初步数据表明多胺途径（限速酶， Odc1) 和表观基因组修饰剂 JMJD3/Kdm6b。我们还提供了证据表明抑制 Odc1-JMJD3轴通过化学抑制剂或基因删除修饰转录组和表观基因组 Th17 细胞（基因组可及性）有利于 Tregs 与中枢神经系统组织炎症的相关性实验性自身免疫性脑脊髓炎（EAE）。根据这些数据我们假设多胺途径是效应子与 Treg 分化的关键代谢和表观遗传调节因子从而影响组织炎症的发展。该途径的关键元件 Odc1- JMJD3轴是一个可以受细胞因子调节、可以感知环境的检查点缺氧等线索，随后调整 T 细胞的代谢和表观基因组状态调节效应细胞与调节性 T 细胞的平衡。我们将通过两个目标来检验这个假设：1）确定多胺生物合成如何限制线粒体氧化磷并促进反向电子传递 EAE 期间中枢神经系统发炎的影响效应器与 Treg 发育； 2) 判断是否聚胺代谢酶 Odc1 干扰 JMJD3 功能以调节 T 基因组可及性在 EAE 发育过程中，细胞更倾向于 Th17 而非 Treg 发育。多胺代谢该通路可能对 T 细胞生物学具有更广泛的影响。因此，我们将重点关注以下内容的相关性： Th17/Treg 平衡背景下发炎中枢神经系统中的 Odc1-JMJD3 轴。拟议的研究高度与人类疾病相关，正如多重之间的显着重叠（约 25%）所反映的那样硬化风险变异和差异调节效应 Th17 与 Treg 分化的基因。