PARP9 and PARP14 in atherosclerosis

 描述（由申请人提供）：巨噬细胞的不受控制的活化促进各种炎性疾病。与巨噬细胞活化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。为了发现作为治疗靶点的巨噬细胞活化的新型调节剂，我们对IFNγ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PARP 9和PARP 14，ADP-核糖基化酶，作为关键候选物。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。基于我们自己的初步发现，这个多学科研究项目将测试PARP 9促进和PARP 14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PARP 9和PARP 14在巨噬细胞活化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PARP 9和PARP 14之间相互作用的新发现，以及它们与促炎性STAT 1和抗炎性STAT 6的关联。具体目标2还将使用质谱和系统生物学来探索PARP 9和PARP 14之间的相互作用通过信号分子的核糖基化调节巨噬细胞活化的机制（例如，STAT1）。我们的研究将揭示巨噬细胞活化的新机制，并提供PARP 9和PARP 14可以作为动脉粥样硬化及其并发症的治疗靶点的概念证明。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.