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.
Nuclear receptor interacting protein 1 (NRIP1, also known as RIP140) is a wide spectrum transcriptional coregulator that is also involved in signal integration of retinoic acid (RA)/vitamin A with other signal pathways, and plays roles in various diseases particularly inflammatory diseases. The major goal of this project is to determine molecular actions of RIP140 in relation to inflammatory diseases and vitamin A signaling. The studies will address key challenges in translational and therapeutic application of RA and facilitate our understanding of vitamin A in health and diseases.
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