PARP9 and PARP14 in atherosclerosis

 描述（由申请人提供）：巨噬细胞不受控制的激活会促进各种炎症性疾病。与巨噬细胞激活相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。为了发现巨噬细胞激活的新调节因子作为治疗靶点，我们对 IFNγ 触发的 M1 和 IL-4 诱导的 M2 巨噬细胞进行了全局蛋白质组学。我们确定 PARP9 和 PARP14（ADP 核糖基化酶）作为关键候选酶。这两种 PARP 的功能尚未得到很好的表征，它们在巨噬细胞生物学或血管疾病中的作用尚不清楚。根据我们自己的初步发现，这个多学科研究项目将测试 PARP9 促进巨噬细胞活化而 PARP14 抑制巨噬细胞活化的新假设。在具体目标 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。我们的初步研究证明了有关 PARP9 和 PARP14 之间相互作用及其与促炎 STAT1 和抗炎 STAT6 之间关系的许多新发现。具体目标 2 还将使用质谱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）的核糖基化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 可以成为动脉粥样硬化及其并发症的治疗靶点提供概念证明。此外，该研究将为各种其他炎症性疾病的共同机制提供新的见解，从而带来令人兴奋的未来方向和临床转化。

 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.