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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.

项目摘要 Th 17细胞在获得性免疫和自身免疫性疾病中发挥重要作用。在正常生理在某些条件下，Th 17细胞产生IL-17 A和IL-17 F以保护粘膜免受细菌和真菌感染。然而，Th 17细胞的失调是炎症性肠病、多发性硬化症和类风湿关节炎Th 17细胞谱系的分化已经被深入研究，并且已经产生了显著的结果。关键转录因子如Irf 4、Batf、Stat 3与谱系- 特异性调节因子RogT定义了Th 17细胞的转录程序和功能。这些监管网络是由IL-6和TGF-β 1诱导的，进一步的IL-23信号通路促进了 Th 17细胞为了确定Th 17特异性调节因子，我们最近进行了全面的ChIP-seq 和RNA-seq研究，发现IIa类Hdacs、Hdac 4和Hdac 7作为候选者，由Stat 3和BET蛋白质转录调节。我们进一步发现，Hdac 4和Hdac 7共定位于不同的转录因子JunB和Bhlhe 40在基因的顺式调节区，以激活Th 17致病性 IL 23 r、Tgfb 3、IL 22、Csf 2基因和IL 10基因在Th 17细胞中的表达分化（IL-6+IL-23+IL-1b）。然而，我们仍然对Hdac 4和Hdac 4的机理了解有限。 Hdac 7在致病性Th 17细胞发育中具有独特的功能。目前还不清楚Hdac 4和Hdac 7是如何工作的。通过调节结肠炎中的Th 17细胞维持和/或可塑性来促进Th 17致病性。我们因此，目的是描述Hdac 4和Hdac 7在Th 17细胞介导的炎症中的作用，并建立 Hdac 4和/或Hdac 7的药理学抑制作为治疗Th 17- 与结肠炎有关