Signaling Status in Lupus

描述(申请人提供)：狼疮是一种复杂的自身免疫性疾病，具有相当高的发病率和死亡率，免疫系统异常会导致器官损伤，影响关节、大脑、皮肤和肾脏。然而，狼疮发病的分子机制很大程度上是未知的。先前的研究表明，狼疮中的免疫细胞，如B细胞、T细胞和髓系细胞在疾病过程中过度增殖和过度活跃。最近的遗传学研究已经发现了许多重要的狼疮基因，包括IRF5、STAT4和IRAK1等先天免疫反应相关基因，BLK、BANK1、Lyn和Ly108等B细胞信号相关基因，以及PTPN22、HLA-DR和PDCD1等T细胞激活相关基因。同时，我们发现PI3K/AKT/mTOR、MEK1/ERK1/2、p38、NF-B、多个Bcl-2家族成员以及细胞周期等几个信号轴在狼疮小鼠模型中存在异常。这一发现很重要，因为它揭示了一些很好的治疗小鼠狼疮的靶点。在完成的工作中，我们已经证明了阻断AKT/mTOR激活可以治疗小鼠狼疮。最近，我还使用CDDO-Me和Nemo结合肽作为治疗剂(手稿正在准备中)，也表明MAPK和NF：B的激活也是很好的治疗靶点。最后，我最近定义了几个T细胞信号通路，它们在小鼠狼疮中也上调(手稿正在准备中)。提出这项研究的另一个重要原因是基于我们最近的整个动态组分析结果，这是令人兴奋的，因为它反映了狼疮淋巴细胞中所有激酶的功能状态。重要的是，这个功能屏幕证实了我们用Western blotts发表的一些数据。此外，这一全面的基因组筛查还揭示了一些新的和重要的信号分子，这些分子可能对指导狼疮的发展具有重要的致病作用。总而言之，这些研究表明，信号分子可能是狼疮的良好治疗靶点。这笔赠款的目标是将这些发现转化为人类系统性红斑狼疮。在这项研究中，我们有两个具体目标。目的：研究Aurora A、Plk1、PKR、RSK3和RIPK3在狼疮小鼠白细胞中的表达。目的：利用“逆相信号阵列”这一综合筛选平台，研究SLE患者外周血白细胞中已建立的高表达信号轴的表达。 公共卫生相关性：叙述：狼疮是一种高度复杂的自身免疫性疾病，其发病机制尚不清楚。我们和其他实验室已经显示了一些信号分子，特别是在狼疮小鼠中上调的激酶。在这项研究中，我们将通过使用新的生化和蛋白质组学方法来验证这些潜在的有趣分子，以便绘制一个可能有助于狼疮发展的信号网络。。

DESCRIPTION (provided by applicant): Lupus is a complex autoimmune disease with substantial morbidity and mortality, where an aberrant immune system causes organ damage affecting the joints, brain, skin and kidneys. However, the molecular mechanism underlying the pathogenesis of lupus is largely unknown. Previous studies have shown immune cells, such as B cells, T cells and myeloid cells in lupus are hyper-proliferative and hyperactive during disease. Recent genetic studies have uncovered quite a few important lupus genes, including innate immune responses related genes, such as IRF5, STAT4 and IRAK1 etc; B cell signaling related genes, such as BLK, BANK1, LYN and Ly108 etc; and T cell activation related genes, such as PTPN22, HLA-DR, and PDCD1 etc. At the same time, we found several signaling axes, including PI3K/AKT/mTOR, MEK1/Erk1/2, p38, NF-:B, multiple Bcl-2 family members, and cell-cycle, to be aberrant in lymphocytes from lupus mouse models compared to normal controls. This finding is important because it has revealed some good therapeutic targets in murine lupus. In the completed work we have shown that blocking AKT/mTOR activation can be therapeutic in murine lupus. Recently, I have also shown that MAPK and NF-:B activation are also good therapeutic targets, using CDDO-me and NEMO-binding peptides as treatment agents (manuscripts in preparation). Finally, I have recently defined several T-cell signaling pathways that are also upregulated in murine lupus (manuscript in preparation). Another important reason to propose this study is based on our recent whole kinome assay results, which is exciting since it reflects the functional status of all kinases in lupus lymphocytes. Importantly, this functional screen confirmed some of our published data using western blots. Besides, this comprehensive kinome screen has also revealed some novel and important signaling molecules which might be of pathogenic importance in guiding lupus development. Collectively, these studies have shown that signaling molecules may be good treatment targets in lupus. The goal of this grant is to translate these findings to human SLE. In this study, we have 2 specific aims. Aim 1: To study the expression of Aurora A, Plk1, PKR, RSK3 and RIPK3 in murine lupus leukocytes, extrapolating from the findings of our recent comprehensive kinome screens. Aim 2: To study the expression of selected signaling axes (already established to be elevated in murine lupus) within the leukocytes of SLE patients, using "Reverse phase signaling array", a comprehensive screening platform. PUBLIC HEALTH RELEVANCE: Narrative: Lupus is a highly complex autoimmune disease and the mechanism of the disease is unknown. We and other laboratories have shown some signaling molecules, particularly kinases are upregulated in lupus mice. In this study, we will validate these potentially interesting molecules by using novel biochemical and proteomic approaches, in order to draw a signaling network that might contribute to the development of lupus. .