The role of PIAS1 in inflammation and immune disorders

描述（由申请人提供）：促炎细胞因子在介导炎症和免疫应答中发挥重要作用。细胞因子功能失调与自身免疫性疾病如关节炎有关。细胞因子通过激活多种信号级联发挥其生物学功能，包括STAT和NF-kB通路。我的长期研究目标是了解细胞因子信号传导和免疫调节。我们已经确定了一个新的蛋白质家族命名为皮亚斯（激活STAT的蛋白质抑制剂），负调控STAT信号。我们最近的研究表明PIAS 1也是NF-κ B的抑制剂，并且PIAS 1在体内控制促炎细胞因子的产生中起重要作用。该提案的总体目标是使用生物化学和遗传学相结合的方法进一步研究PIAS 1在NF-κ B信号传导、促炎细胞因子产生和关节炎中的机制和功能。首先，我们将研究PIAS 1介导的NF- kB抑制的分子机制。我们将讨论PIAS 1介导的抑制NF-κ B依赖基因的特异性。我们将研究PIAS 1的SUMOE 3连接酶活性在NF-κ B信号传导中的重要性.我们还将研究其他皮亚斯蛋白参与NF-κ B的调节。其次，我们将解决PIAS 1介导的促炎细胞因子产生的调节机制。我们将研究PIAS 1介导的调节细胞因子的产生在转录和翻译后水平。第三，我们将使用各种动物模型来研究PIAS 1在关节炎发病机制中的体内作用。我们将研究PIAS 1介导的关节炎模型中的作用的可能机制。我们还将研究STAT 1信号在关节炎发病机制中的参与。这些研究将进一步了解PIAS 1在炎症和免疫疾病中的作用，并可能确定治疗干预的新靶点。

DESCRIPTION (provided by applicant): Pro-inflammatory cytokines play important roles in mediating inflammation and immune responses. Dysregulation of cytokine functions has been implicated in autoimmune diseases, such as arthritis. Cytokines exert their biological functions by activating multiple signaling cascades, including STAT and NF-kB pathways. My long-term research goal is to understand cytokine signaling and immune regulation. We have identified a novel family of proteins named PIAS (protein inhibitor of activated STAT), which negatively regulates STAT signaling. Our recent studies revealed that PIAS1 is also an inhibitor of NF- kB , and that PIAS1 plays an important role in controlling the pro-inflammatory cytokine production in vivo. The overall goal of this proposal is to further study the mechanism and function of PIAS1 in NF-kB signaling, proinflammatory cytokine production and arthritis using combined biochemical and genetic approaches. First, we will study the molecular mechanism of PIAS1-mediated inhibition on NF- kB. We will address the specificity of PIAS1-mediated inhibition on NF- kB -dependent genes. We will examine the importance of SUMO E3 ligase activity of PIAS1 in NF- kB signaling. We will also study the involvement of other PIAS proteins in the regulation of NF- kB . Second, we will address the mechanism of PIAS1-mediated regulation of pro-inflammatory cytokine production. We will study PIAS1-mediated regulation of cytokine production at both transcriptional and posttranslational levels. Third, we will address the in vivo role of PIAS1 in the pathogenesis of arthritis using various animal models. We will examine the possible mechanisms of PIAS1- mediated action in arthritis models. We will also study the involvement of STAT1 signaling in arthritis pathogenesis. These studies will provide further understanding of the role of PIAS1 in inflammation and immune diseases and may identify novel targets for therapeutic interventions.