Ligand-dependent regulation of the nuclear receptor REV-ERBa in TH17 cell development and inflammation

TH17 细胞发育和炎症中核受体 REV-ERBa 的配体依赖性调节

• 批准号: 10608664
• 负责人: Laura A Solt
• 金额: $ 59.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608664
• 关键词: Affect; Aggravated Colitis; Automobile Driving; Binding; Cell Nucleus; Cells; Chronic; Colitis; Consensus; DNA; Data; Development; Disease; Endocrine; Enzymes; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; Heme; Homeostasis; Inflammation; Inflammatory; Inflammatory Response; Ligands; Lipids; Mediating; Metabolic; Molecular Biology; Molecular Immunology; Nuclear Receptors; Pathogenesis; Pathogenicity; Pharmacologic Substance; Physiological; Process; Proteins; Regulation; Reporting; Repression; Response Elements; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Source; T-Lymphocyte; Tissues; Transcription Coactivator; Transcription Repressor; Translating; Vitamins; dietary heme; extracellular; genetic approach; genetic corepressor; genetic signature; gut dysbiosis; heme biosynthesis; in vivo; insight; knock-down; member; mouse model; receptor; response; small molecule; transcription factor

SUMMARY As ligand-regulated transcription factors, nuclear receptors (NRs) evolved to respond to natural small molecules, such as vitamins and lipids, translating endocrine and metabolic signals into changes in gene expression. Our data, that ligand-dependent REV-ERB activity may regulate TH17 cell inflammatory responses, suggests that the REV-ERBs natural endogenous ligand, heme, may function as a REV-ERB-dependent signaling molecule in TH17 cells. Given the evidence that both intracellular and extracellular ligands regulate NR activity in TH17 cells, defining ligand mechanisms of action and/or understanding the source and effects of heme- dependent REV-ERB activity in TH17 cells may reveal signaling pathways underlying homeostasis vs. pathogenesis. Our preliminary data suggests that REV-ERBa/heme dependent signaling may be required for protection from inflammation in the gut (colitis). This coincides with recent evidence demonstrating that dietary heme induces gut dysbiosis and aggravates colitis. Therefore, understanding how ligands, like heme, regulate the REV-ERBs would be particularly valuable for understanding how environmental signals influence TH17 cells and inflammation. Our overarching goals are to define the role of heme as an endocrine signaling molecule and elucidate the ligand-mediated mechanisms that regulate REV-ERBa’s transcriptional activity and interacting partners, thus driving repressive functions in TH17 cells during inflammatory processes. We will accomplish this goal by identify heme’s role as a REV-ERBa-dependent signaling molecule in TH17 cells; establishing whether heme-dependent REV-ERBa activity affects TH17-mediated inflammation in vivo; and defining how ligands affect the REV-ERBa’s transcriptional partners and repressive function in TH17 cells. The proposed studies will address fundamental questions regarding ligand-dependent REV-ERBa activity. Importantly, these insights will be particularly valuable in understanding TH17-mediated disease development and may inform on future pharmaceutical approaches.

摘要 作为配体调节的转录因子，核受体(NRs)进化为对天然小分子的反应 维生素和脂类等分子，将内分泌和代谢信号转化为基因变化 表情。我们的数据表明，配体依赖的Rev-ERB活性可能调节TH17细胞的炎症反应， 提示REV-ERBS天然的内源性配体--血红素可能具有REV-ERB依赖的功能 TH17细胞中的信号分子。鉴于有证据表明细胞内和细胞外的配体都调节NR 在TH17细胞中的活性，定义配基的作用机制和/或理解血红素的来源和影响- 依赖于REV-ERB活性的TH17细胞可能揭示了与动态平衡相关的信号通路。 发病机制。我们的初步数据表明，REV-ERBA/血红素依赖的信号转导可能是 防止肠道发炎(结肠炎)。这与最近的证据表明，饮食 血红素会导致肠道生态失调，加重结肠炎。因此，了解配体，如血红素，是如何调节 REV-ERBS对于了解环境信号如何影响TH17细胞特别有价值 和炎症。我们的首要目标是定义血红素作为内分泌信号分子的作用和 阐明配体介导的调节REV-Erba转录活性和相互作用的机制 从而在炎症过程中驱动TH17细胞的抑制功能。我们会做到这一点的 目的是通过确定血红素在TH17细胞中作为REV-ERBA依赖的信号分子的作用；确定 血红素依赖的REV-ERBA活性影响体内TH17介导的炎症；并确定配体如何影响 Rev-Erba在TH17细胞中的转录伙伴和抑制功能。拟议的研究将涉及 关于配体依赖的REV-ERBA活性的基本问题。重要的是，这些见解将是 在理解TH17介导的疾病发展方面特别有价值，并可能为未来提供信息 制药方面的方法。