PARP activity in allergic inflammation

摘要 辅助性T细胞2(Th2)介导对寄生虫的免疫并促进过敏性疾病，而 Th1细胞提供对细胞内病原体的免疫力，并启动炎症。干扰素-发挥作用 在Th1反应中起主要作用但抑制Th2细胞的发展，而IL-4促进Th2 免疫和抑制Th1分化。转录因子STAT1和STAT6是关键 细胞因子干扰素-α和白介素4的信号分子。我们已经确定了一部小说 转录辅因子，CoaSt6(Stat6的协作者)，特异性增强Stat6，但不 STAT1依赖的转录。由于存在宏结构域和PARP(聚 ADP-核糖聚合酶)催化结构域，CoaSt6属于PARP蛋白家族， 也称为PARP-14。我们已经证明CoaSt6/PARP-14含有PARP催化 活性和初步数据显示，抑制PARP活性具有药理作用 抑制剂针对的是IL-4，而不是干扰素介导的基因诱导。此外，T的分化 在PARP抑制剂存在的情况下，辅助细胞进入Th2表型的效率较低。我们的 初步数据还表明，鼻腔给药PARP抑制剂对 哮喘小鼠模型可减少肺部炎症。此应用程序的目标是 阐明CoaSt6/PARP-14发挥作用的分子机制 在辅助性T细胞免疫中的作用。这一提议的假设是，宏观和 CoaSt6/PARP-14的PARP结构域使用一种独特的机制来调节转录， PARP活性对Th2反应的要求可作为治疗的靶点 哮喘。为了解决这一假设，我们将使用生化和分子生物学工具。 明确CoaSt6/PARP-14调控转录的机制。用一只老鼠 我们将确定CoaSt6/PARP-14在Th2介导的过敏性哮喘中的作用。此外， 我们将研究在特应性气道小鼠模型中是否抑制PARP活性 高反应性能够缓解这种疾病。综上所述，建议的研究包括 目的是了解一种新的转录辅因子的生物学功能，并进行事实测试 过敏性哮喘治疗的可行性。

ABSTRACT T helper 2 (Th2) cells mediate immunity to parasites and promote allergic disease, while Th1 cells provide immunity to intracellular pathogens and initiate inflammation. IFN- plays a major role in Th1 responses but inhibits the development of Th2 cells, while IL-4 promotes Th2 immunity and inhibits Th1 differentiation. The transcription factors Stat1 and Stat6 are the key signaling molecules for the cytokines IFN- and IL-4 respectively. We have identified a novel transcriptional cofactor, CoaSt6 (Collaborator of Stat6) that specifically enhances Stat6 but not Stat1 dependent transcription. Owing to the presence of macro domains and the PARP (poly ADP-ribose polymerase) catalytic domain, CoaSt6 belongs to the PARP family of proteins and is also called PARP-14. We have demonstrated that CoaSt6/PARP-14 contains PARP catalytic activity and preliminary data shows that inhibition of PARP activity with a pharmacological inhibitor targets IL-4 but not IFN- mediated gene induction. Furthermore, the differentiation of T helper cells into the Th2 phenotype is less efficient in the presence of PARP inhibitors. Our preliminary data also demonstrates that the intranasal administration of a PARP inhibitor to a mouse model of asthma reduces inflammation in the lung. The goal of this application is to elucidate the molecular mechanism by which CoaSt6/PARP-14 functions and to determine its role in T helper cell mediated immunity. The hypothesis for this proposal is that the macro and PARP domains of CoaSt6/PARP-14 employ a unique mechanism to regulate transcription and, the requirement of PARP activity for Th2 responses can be used as a therapeutic target for asthma. To address this hypothesis we will employ biochemical and molecular biological tools to define the mechanism by which CoaSt6/PARP-14 regulates transcription. Using a murine model we will determine the role of CoaSt6/PARP-14 in Th2 mediated allergic asthma. Further, we will investigate if inhibition of PARP activity in a mouse model of atopic airway hyperresponsiveness is able to alleviate this disease. Taken together, the proposed studies are aimed to understand the biological function of a novel transcriptional cofactor and will in fact test the feasibility of a therapy for allergic asthma.