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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