Studies of nuclear receptor corepressor, NRIP1, in vitamin A signaling pathways

视黄酸（RA）是维生素A的生物活性成分，是多种生物过程所必需的。RA主要通过与核RA受体（RAR）和类维生素A受体X（RXR）结合来调节基因表达。但是RAR和RXR的活动最终取决于辅调节因子的募集。该项目是通过鉴定一种名为受体相互作用蛋白140（RIP 140）的RA依赖性RAR辅助调节因子而启动的，也称为核受体相互作用蛋白1（Nrip 1），其调节包括所有核受体在内的广谱转录因子。RIP 140在以下方面是独特的：i）在染色质重塑中的广谱活性，和ii）调节其性质和与疾病的相关性的广泛的翻译后修饰（PTM）。上次进展（2013-2017年）已发表16篇论文，其中报告：i）RIP 140在代谢和先天免疫中的活性（巨噬细胞M1/M2极化），ii）RA在激活M2基因Arg 1中的强活性，iii）触发RIP 140的PTM的信号，和iv）RA和RIP 140在通过调节巨噬细胞M1-M2极化和促进M2基因Arg 1来控制慢性炎性病症如伤口愈合中的新治疗潜力。基于这些发现，假设抑制RIP 140水平和添加RA可以通过促进先天免疫循环完成（M1-M2极化）和促进组织修复中M2的关键效应基因Arg 1来协同（相加）增强抗炎。这两个目标是：i）推进翻译研究，确定抑制RIP 140和应用RA是否以及如何协同促进抗炎以改善伤口愈合，以及ii）进行深入和全面的研究，回答RIP 140如何在单细胞分辨率下调节巨噬细胞极化潜力以及RA如何协调多个基因调控事件（染色质重塑、转录和偶联的RNA加工）来促进Arg 1表达以有效地伤口愈合。完成这些研究将为设计更有效的策略来管理与内源性类维生素A/RA状态和炎症状态相关的疾病以及开发RA作为更有效的治疗药物提供进一步的见解。

Retinoic acid (RA), the biologically active ingredient of vitamin A, is essential for a variety of biological processes. RA acts, primarily, by binding to nuclear RA receptor (RAR) and retinoid receptor X (RXR) to regulate gene expression. But the activities of RAR and RXR ultimately depend on the recruitment of coregulators. This project was initiated by the identification of an RA-dependent RAR coregulator named Receptor Interacting Protein 140 (RIP140), also known as Nuclear Receptor Interacting Protein 1 (Nrip1), which regulates a wide spectrum of transcription factors including all nuclear receptors. RIP140 is unique for i) wide spectrum activity in chromatin remodeling, and ii) extensive post-translational modifications (PTMs) that regulate its properties and relevance to diseases. Previous progress (2013-2017) related to this renewal has been published in 16 papers, which report: i) RIP140's activity in metabolism and innate immunity (macrophage M1/M2 polarization), ii) a robust activity of RA in activating M2 gene Arg1, iii) signals triggering RIP140's PTMs, and iv) new therapeutic potential of RA and RIP140 in managing chronic inflammatory conditions such as wound healing, via modulating macrophage M1-M2 polarization and boosting M2 gene Arg1. Based upon these findings, it is hypothesized that dampening the RIP140 level and adding RA can synergistically (additively) enhance anti-inflammation by facilitating innate immune cycle completion (M1-M2 polarization) and boosting a critical effecter gene for M2 in tissue repair, Arg1. The two aims are: i) to advance translational studies determining whether and how dampening RIP140 and applying RA can synergistically boost anti-inflammation to improve wound healing, and ii) to pursue in-depth and holistic studies answering how RIP140 modulates macrophage polarization potential at the single cell resolution and how RA orchestrates multiple gene regulatory events (chromatin remodeling, transcription and coupled RNA processing) to promote Arg1 expression for effective wound healing. Completing these studies will provide further insight for designing more efficient strategies in managing diseases related to the endogenous retinoid/RA status and inflammatory state, and for developing RA as a more effective therapeutic agent.