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，对多种生物过程至关重要。RA主要通过与核RA受体（RAR）和类视黄醇受体X （RXR）结合来调节基因表达。但RAR和RXR的活动最终取决于共同监管者的招募。该项目是由一个名为受体相互作用蛋白140 （RIP140）的ra依赖性RAR共调节因子的鉴定启动的，也称为核受体相互作用蛋白1 (Nrip1)，它调节包括所有核受体在内的广泛转录因子。RIP140的独特之处在于i)在染色质重塑中的广谱活性，以及ii)广泛的翻译后修饰（PTMs）调节其特性和与疾病的相关性。与这一更新相关的先前进展（2013-2017）已发表在16篇论文中，其中报道了：i) RIP140在代谢和先天免疫（巨噬细胞M1/M2极化）中的活性，ii) RA激活M2基因Arg1的强大活性，iii)触发RIP140的PTMs信号，以及iv) RA和RIP140通过调节巨噬细胞M1-M2极化和促进M2基因Arg1，在治疗伤口愈合等慢性炎症疾病方面的新治疗潜力。基于这些发现，我们假设抑制RIP140水平和添加RA可以通过促进先天免疫周期完成（M1-M2极化）和促进M2在组织修复中的关键效应基因Arg1来协同（加性）增强抗炎能力。这两个目标是：i)推进转化研究，确定抑制RIP140和应用RA是否以及如何协同促进抗炎，以改善伤口愈合；ii)深入和全面地研究RIP140如何在单细胞分辨率上调节巨噬细胞极化电位，以及RA如何协调多基因调控事件（染色质重塑、转录和偶联RNA加工）促进Arg1表达，以促进有效的伤口愈合。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.