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

维甲酸(RA)是维生素A的生物活性成分，在多种生物过程中都是必不可少的。RA主要通过与RA核受体(RAR)和维甲酸X受体(RXR)结合来调节基因表达。但RAR和RXR的活动最终取决于联合监管机构的招募。该项目是由发现一种名为受体相互作用蛋白140(RIP140)的RA依赖的RAR辅助调节因子发起的，该蛋白也被称为核受体相互作用蛋白1(Nrig1)，它调节包括所有核受体在内的广泛范围的转录因子。RIP140是独一无二的：1)染色质重塑中的广谱活性；2)广泛的翻译后修饰(PTM)，调节其性质和与疾病的相关性。与这一更新相关的先前进展(2013年至2017年)已发表在16篇论文中，这些论文报道：i)RIP140在代谢和先天免疫(巨噬细胞M1/M2极化)中的S活性；ii)RA在激活M2基因Arg1方面的强大活性；iii)触发RIP140‘S PTM的信号；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，在控制伤口愈合等慢性炎症方面的新的治疗潜力。根据这些发现，假设降低RIP140水平和加入RA可以协同(相加)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Arg1来增强抗炎作用。这两个目标是：i)推进翻译研究，确定抑制RIP140和应用RA是否以及如何协同增强抗炎作用以促进伤口愈合，以及ii)进行深入和全面的研究，以回答RIP140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节事件(染色质重塑、转录和耦合RNA处理)以促进Arg1的表达以实现有效的伤口愈合。完成这些研究将为设计更有效的策略来管理与内源性视黄醇/类风湿关节炎状态和炎症状态相关的疾病，以及将类风湿关节炎发展为更有效的治疗剂提供进一步的见解。

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.