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

基本信息

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
项目类别：
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

项目摘要

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.

概括作为配体调节的转录因子，核受体 (NR) 进化出对天然小分子的反应分子，如维生素和脂质，将内分泌和代谢信号转化为基因的变化我们的数据表明，配体依赖性 REV-ERB 活性可能调节 TH17 细胞炎症反应，表明 REV-ERB 天然内源配体血红素可能作为 REV-ERB 依赖的 TH17 细胞中的信号分子有证据表明细胞内和细胞外配体均调节 NR。 TH17 细胞中的活性，定义配体作用机制和/或了解血红素的来源和作用 TH17 细胞中依赖的 REV-ERB 活性可能揭示稳态与稳态之间的信号通路。我们的初步数据表明，REV-ERBa/血红素依赖性信号传导可能是发病机制所必需的。防止肠道炎症（结肠炎），这与最近的证据表明饮食一致。血红素会引起肠道菌群失调并加重结肠炎，因此，了解血红素等配体如何调节。 REV-ERB 对于了解环境信号如何影响 TH17 细胞特别有价值我们的首要目标是确定血红素作为内分泌信号分子的作用和阐明调节 REV-ERBa 转录活性和相互作用的配体介导机制合作伙伴，从而在炎症过程中驱动 TH17 细胞的抑制功能。通过确定血红素在 TH17 细胞中作为 REV-ERBa 依赖性信号分子的作用来实现目标；血红素依赖性 REV-ERBa 活性影响 TH17 介导的体内炎症；并定义配体如何影响；拟议的研究将解决 REV-ERBa 的转录伙伴和 TH17 细胞中的抑制功能。重要的是，这些见解将是关于配体依赖性 REV-ERBa 活性的基本问题。对于理解 TH17 介导的疾病发展特别有价值，并可能为未来提供信息制药方法。