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

• 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
• 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

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.

项目总结 Th17细胞在获得性免疫和自身免疫性疾病中发挥重要作用。在正常生理状态下 在这种情况下，Th17细胞产生IL-17A和IL-17F，以保护粘膜免受细菌和真菌的感染。 然而，Th17细胞的失调是炎症性肠病、多发性硬化症和 类风湿关节炎。Th17细胞系的分化已被深入研究并取得了成果 取得了重大成果。IRF4、BATF、STAT3等关键转录因子与谱系的协同作用-- 特异性调节因子RorgT定义Th17细胞的转录程序和功能。这些监管规定 IL-6和转化生长因子-β1诱导的网络，进一步的IL-23信号通路促进肿瘤的发展。 致病Th17细胞。为了识别Th17特定的调节器，我们最近进行了全面的芯片序列 和对Th17细胞的RNA-SEQ研究，发现IIa类HDAC4和HDAC7是候选的 受STAT3和BET蛋白转录调控。我们进一步发现，HDAC4和HDAC7与 不同转录因子JunB和Bhlhe40位于基因顺式调控区，激活Th17致病因子 致病Th17细胞中的抑制基因(Il23r、TGFB3、Il22、CSF2)和抑制基因(Il10 分化(IL-6+IL-23+IL-1b)。然而，我们对HDAC4和HDAC4的机械理解仍然有限 HDAC7在致病Th17细胞的发育过程中发挥着重要作用。目前也不清楚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的致病作用。我们 目的阐明HDAC4和HDAC7在Th17细胞介导的炎症反应中的作用，并建立 药物抑制HDAC4和/或HDAC7作为治疗Th17的新策略的可行性 相关性结肠炎。