Regulation of TH17 plasticity and stemness by mTORC1

mTORC1 对 TH17 可塑性和干性的调节

基本信息

批准号：
10094053
负责人：
Hongbo Chi
金额：
$ 44.88万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-13 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10094053
关键词：
ATAC-seq Affect Allergic American Autoimmune Autoimmune Diseases Biological Assay Biological Markers CD4 Positive T Lymphocytes Cell Differentiation process Cell Fate Control Cells Cellular biology Central Nervous System Diseases Characteristics Data Demyelinating Diseases Development Disease Dissection Environment Enzymes Equilibrium Exhibits Experimental Autoimmune Encephalomyelitis Genetic Genetic Transcription Glycolysis Goals Heterogeneity Hexokinase 2 Human Immune Immune signaling Immune system Impairment Inflammatory Interferons Link Maintenance Mediating Metabolic Metabolic Control Metabolic Pathway Metabolism Modeling Molecular Multiple Sclerosis Mus Mutant Strains Mice Myelin Sheath Pathogenesis Pathogenicity Pathway interactions Phenotype Play Process Program Description Proteomics Raptors Regulation Research Role Signal Transduction System Systems Biology T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Technology Testing Th1 Cells Therapeutic Tissues Up-Regulation adaptive immunity autoimmune inflammation autoreactive T cell biological systems cholesterol biosynthesis cytokine effector T cell in vivo innovative technologies insight metabolomics mouse model neuroinflammation novel prevent programs response single-cell RNA sequencing stem cells stem-like cell stemness therapeutic target trait

项目摘要

Program Description/Abstract Lineage commitment and maintenance are fundamental processes in a variety of biological systems. In the immune system, dysregulated T cell responses are the cause of many allergic and inflammatory disorders. TH17 cells play a key pathogenic role in Multiple sclerosis (MS) and its murine model, experimental autoimmune encephalomyelitis (EAE). A unique feature of TH17 cells is their inherent plasticity that endows mature effector TH17 cells with characteristics of other T cell subsets especially TH1 cells, but how this process is controlled and its functional significance remain elusive. Coordination of T cell metabolic programs with cell fate decisions is a fundamental process in adaptive immunity, but how metabolic pathways intersect with immune signals in T cell fate decisions and autoimmune dysregulation is poorly defined. In particular, the function of metabolic programs in effector T cell plasticity and pathogenicity remains essentially unexplored. We hypothesize that the inherent heterogeneity of TH17 cells underlies their lineage plasticity; the balance between terminal differentiation and sustained stemness depends upon mTORC1 signaling and metabolic reprogramming, and contributes to autoimmune inflammation. Aim 1. Determine transcriptional mechanisms and developmental trajectory underlying TH17 terminal differentiation and stemness. Aim 2. Establish the signaling and metabolic mechanisms of mTORC1 in TH17 responses. Aim 3. Establish metabolic control and signaling circuits of TH17 plasticity. There has been little description of molecular pathways regulating TH17 lineage plasticity. We argue that insight into metabolic control of TH17 plasticity could establish a new paradigm of T cell fate control mechanisms, and manifest legitimate therapeutic opportunities for autoimmune diseases.

项目描述/摘要谱系承诺和维持是各种生物系统中的基本过程。在免疫系统、T 细胞反应失调是许多过敏和炎症性疾病的原因。 TH17 细胞在多发性硬化症 (MS) 及其小鼠模型、实验中发挥关键致病作用自身免疫性脑脊髓炎（EAE）。 TH17 细胞的一个独特特征是其固有的可塑性，赋予成熟的效应 TH17 细胞具有其他 T 细胞亚群尤其是 TH1 细胞的特征，但这个过程是如何进行的受到控制，其功能意义仍然难以捉摸。 T 细胞代谢程序与细胞的协调命运决定是适应性免疫的一个基本过程，但代谢途径如何与 T 细胞命运决定和自身免疫失调中的免疫信号尚不清楚。特别是，代谢程序在效应 T 细胞可塑性和致病性中的功能基本上尚未被探索。我们假设 TH17 细胞固有的异质性是其谱系可塑性的基础；终末分化和持续干性之间的平衡取决于 mTORC1 信号传导和代谢重编程，并导致自身免疫性炎症。目标 1. 确定转录机制和发育轨迹潜在的 TH17 终末分化和干性。目标 2. 建立信号传导和代谢 mTORC1 在 TH17 反应中的机制。目标 3. 建立 TH17 的代谢控制和信号通路可塑性。关于调节 TH17 谱系可塑性的分子途径的描述很少。我们争论对 TH17 可塑性代谢控制的深入了解可以建立 T 细胞命运控制的新范式机制，并显示自身免疫性疾病的合法治疗机会。