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.

项目摘要/摘要自身免疫组织炎症取决于效应子和调节性T细胞之间的平衡。在自身免疫反应期间，效应T细胞超增殖，产生促炎性细胞因子并抑制导致炎症的调节T细胞的扩张和产生。细胞因子玩在此过程中的关键作用，但是其他因素，例如代谢和氧气张力等物理因素，组织微环境中的pH和空间在调节效应方与Treg中同样重要平衡。但是，由于局限性可用的细胞编号和当前的代谢技术。我们开发了一种新颖的计算算法称为指南针，可以使用单细胞RNASEQ数据预测细胞的代谢状态。由该工具促进，我们确定多胺代谢是TH17致病性的主要驱动力细胞。本文中，我们观察到ODC1抑制可以通过增加来调节线粒体功能线粒体复杂稳定性基因具有效应T细胞功能的潜在后果。更远，我们的初步数据表明多胺途径之间有联系（速率限制酶，， ODC1）和表观基因组修饰符JMJD3/KDM6B。我们还提供了抑制化学抑制剂或遗传缺失的ODC1-JMJD3轴修饰了转录组和表观基因组 Th17细胞的（基因组可及性）有利于Tregs，与CNS中的组织炎症相关实验性自身免疫性脑脊髓炎（EAE）。基于这些数据，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剂从而影响组织炎症的发展。路径的关键要素，odc1- JMJD3轴是一个可以通过细胞因子调节的检查点，并且可以感知环境诸如缺氧以及随后将T细胞的代谢和表观基因组状态调整为调节效应子与调节性T细胞平衡。我们将以两个目的检验该假设：1）确定多胺生物合成如何限制线粒体oxphos并促进反向电子传输到 EAE期间发炎的中枢神经系统的影响力效应子与Treg发育； 2）确定多胺是否代谢酶ODC1干扰JMJD3功能以调节t的基因组可及性在EAE发育过程中，有利于Th17的细胞比Treg的发展。多胺代谢途径可能对T细胞生物学具有更广泛的意义。因此，我们将专注于在Th17/Treg平衡的背景下，odc1-jmjd3轴发炎的中枢神经系统发炎。拟议的研究高度与人类疾病相关，如多重重叠（约25％）所反映的硬化症风险变异和基因差异调节效应子Th17与Treg分化。