PARP9 and PARP14 in atherosclerosis

 描述(申请人提供)：巨噬细胞不受控制的激活促进各种炎症性疾病。与巨噬细胞激活有关的最具破坏性的疾病包括动脉粥样硬化，这是一种全球健康负担。为了发现新的巨噬细胞激活调节因子作为治疗靶点，我们对干扰素γ触发的M1和IL-4诱导的M2巨噬细胞进行了整体蛋白质组学研究。我们确定了ADP核糖化酶PARP9和PARP14为关键候选基因。这两个PARP的功能尚未得到很好的描述，它们在巨噬细胞生物学或血管疾病中的作用也不清楚。基于我们自己的初步发现，这一多学科研究项目将检验PARP9促进和PARP14抑制巨噬细胞激活这一新的假设。在特定的目标1和2中，我们将使用小鼠模型来研究PARP9和PARP14在巨噬细胞激活和动脉粥样硬化中的作用。我们的初步研究已经证明了许多关于PARP9和PARP14之间相互作用的新发现，以及它们与促炎STAT1和抗炎STAT6的关系。特殊目的2还将使用质谱学和系统生物学来探索PARP9和PARP14之间的相互作用通过信号分子(例如STAT1)的核糖化来调节巨噬细胞激活的机制。我们的研究将揭示巨噬细胞激活的新机制，并为PARP9和PARP14可作为动脉粥样硬化及其并发症的治疗靶点的概念提供证据。此外，这项研究将为各种其他炎症性疾病的共同机制提供新的见解，导致令人兴奋的未来方向和临床翻译。

 DESCRIPTION (provided by applicant): Uncontrolled activation of macrophages promotes various inflammatory diseases. The most devastating diseases linked to macrophage activation include atherosclerosis, a global health burden. To discover novel regulators of macrophage activation as therapeutic targets, we performed global proteomics on IFNγ- triggered M1 and IL-4-induced M2 macrophages. We identified PARP9 and PARP14, ADP-ribosylation enzymes, as key candidates. The functions of these two PARPs have not yet well characterized and their roles in macrophage biology or vascular disease are unknown. Based on our own preliminary findings, this multidisciplinary research project will test the novel hypothesis that PARP9 promotes and PARP14 suppresses macrophage activation. In Specific Aims 1 and 2, we will use mouse models to examine the role of PARP9 and PARP14 in macrophage activation and atherosclerosis. Our pilot studies have demonstrated many new findings on the interplay between PARP9 and PARP14 and their associations with pro-inflammatory STAT1 and anti-inflammatory STAT6. Specific Aim 2 also will use mass spectrometry and systems biology to explore the mechanisms by which the interactions between PARP9 and PARP14 regulate macrophage activation via ribosylation of signaling molecules (e.g., STAT1). Our study will reveal novel mechanisms of macrophage activation and provide a proof of concept that PARP9 and PARP14 can be therapeutic targets for atherosclerosis and its complications. Furthermore, the study will offer new insight into the shared mechanisms for various other inflammatory diseases, leading to exciting future directions and clinical translation.