Role of Class IIa HDACs HDAC4 and HDAC7 in Pathogenic Th17 Cell Development and Colitis

IIa 类 HDAC HDAC4 和 HDAC7 在致病性 Th17 细胞发育和结肠炎中的作用

基本信息

批准号：
10557888
负责人：
Kalung Cheung
金额：
$ 42.25万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557888
关键词：
Autoimmune Diseases Bacterial Infections Binding C-terminal CD4 Positive T Lymphocytes Cell Differentiation process Cell Lineage Cell Maintenance Cells ChIP-seq Chemicals Chromatin Colitis Colon Colonic inflammation Communities Complex Data Development Disease Enzymes Genes Genetic Transcription HDAC4 gene HDAC7 histone deacetylase Health Helper-Inducer T-Lymphocyte Histone Deacetylase Histone Deacetylase Inhibitor Human IL10 gene IL17 gene Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-6 Lamina Propria Malignant Neoplasms Maps Mediating Modeling Molecular Mucous Membrane Multiple Sclerosis Mus Mycoses N-terminal Nucleic Acid Regulatory Sequences Outcome Pathogenicity Patients Physiological Play Proteins Regulation Regulator Genes Regulatory Element Regulatory T-Lymphocyte Repression Research Rheumatoid Arthritis Role Signal Pathway T-Cell Development T-Lymphocyte Therapeutic Transcriptional Regulation adaptive immunity cell type cytokine effective therapy empowerment gene repression genetic approach gut inflammation inhibitor interleukin-23 mesenteric lymph node migration murine colitis novel novel therapeutic intervention pharmacologic programs recruit single-cell RNA sequencing transcription factor transcriptome sequencing translational potential virulence gene

项目摘要

PROJECT SUMMARY Th17 cells play important roles in adaptive immunity and autoimmune diseases. In normal physiological conditions, Th17 cells produce IL-17A and IL-17F to protect the mucosa from bacterial and fungal infections. Dysregulation of Th17 cells, however, is responsible for inflammatory bowel diseases, multiple sclerosis and rheumatoid arthritis. Differentiation of Th17 cell lineage has been investigated intensively and has yielded significant results. The cooperation of key transcriptional factors such as Irf4, Batf, Stat3 together with lineage- specific regulator RorgT defines the transcriptional program and function of Th17 cells. These regulatory networks are induced by IL-6 and TGF-b1, and further IL-23 signaling pathways promote the development of pathogenic Th17 cells. To identify Th17-specific regulators, we recently conducted comprehensive ChIP-seq and RNA-seq studies of Th17 cells and discovered Class IIa Hdacs Hdac4 and Hdac7 as candidates that are transcriptionally regulated by Stat3 and BET proteins. We further found that Hdac4 and Hdac7 co-localize with distinct transcription factors JunB and Bhlhe40 on cis-regulatory regions of genes, to activate Th17 pathogenic genes (Il23r, Tgfb3, Il22, Csf2) and repress regulatory gene (Il10), respectively, during pathogenic Th17 cell differentiation (IL-6+IL-23+IL-1b). However, we still have limited mechanistic understanding how Hdac4 and Hdac7 function distinctly in pathogenic Th17 cell development. It is also unclear how Hdac4 and Hdac7 facilitate Th17 pathogenicity through the regulation of Th17 cell maintenance and/or plasticity in colitis. We therefore aim to delineate the role of Hdac4 and Hdac7 in Th17 cell-mediated inflammation, and establish the feasibility of pharmacological inhibition of Hdac4 and/or Hdac7 as a novel therapeutic strategy to treat Th17- related colitis.

项目概要 Th17细胞在适应性免疫和自身免疫性疾病中发挥重要作用。在正常生理情况下在这种情况下，Th17 细胞会产生 IL-17A 和 IL-17F，以保护粘膜免受细菌和真菌感染。然而，Th17 细胞失调会导致炎症性肠病、多发性硬化症和类风湿关节炎。 Th17 细胞谱系的分化已被深入研究并产生了取得了显着的成果。 Irf4、Batf、Stat3 等关键转录因子与谱系的协同作用特定调节因子 RorgT 定义 Th17 细胞的转录程序和功能。这些监管 IL-6和TGF-b1诱导网络，进一步的IL-23信号通路促进网络的发展致病性 Th17 细胞。为了确定 Th17 特异性调节因子，我们最近进行了全面的 ChIP-seq 对 Th17 细胞进行 RNA-seq 研究，发现 IIa 类 Hdacs Hdac4 和 Hdac7 作为候选者转录受 Stat3 和 BET 蛋白调节。我们进一步发现 Hdac4 和 Hdac7 与基因顺式调控区的不同转录因子 JunB 和 Bhlhe40，激活 Th17 致病性在致病性 Th17 细胞中分别抑制基因 (Il23r、Tgfb3、Il22、Csf2) 和抑制调节基因 (Il10) 分化（IL-6+IL-23+IL-1b）。然而，我们对 Hdac4 和 Hdac4 的机制了解仍然有限。 Hdac7 在致病性 Th17 细胞发育中发挥着独特的作用。还不清楚 Hdac4 和 Hdac7 如何通过调节结肠炎中 Th17 细胞的维持和/或可塑性来促进 Th17 致病性。我们因此，旨在描述 Hdac4 和 Hdac7 在 Th17 细胞介导的炎症中的作用，并建立 Hdac4 和/或 Hdac7 的药物抑制作为治疗 Th17-的新治疗策略的可行性相关结肠炎。