Signaling Status in Lupus

描述（由申请人提供）：狼疮是一种复杂的自身免疫性疾病，具有很高的发病率和死亡率，其中异常的免疫系统导致器官损伤，影响关节，大脑，皮肤和肾脏。然而，狼疮发病的分子机制在很大程度上是未知的。先前的研究表明，狼疮患者的免疫细胞，如B细胞、T细胞和骨髓细胞，在疾病期间具有超增殖和过度活跃的特征。近年来的遗传学研究发现了不少重要的狼疮基因，包括先天免疫应答相关基因，如IRF5、STAT4、IRAK1等；B细胞信号传导相关基因，如BLK、BANK1、LYN、Ly108等；T细胞活化相关基因，如PTPN22、HLA-DR、PDCD1等。同时，我们发现与正常对照组相比，狼疮小鼠模型淋巴细胞中PI3K/AKT/mTOR、MEK1/Erk1/2、p38、NF-:B、多个Bcl-2家族成员和细胞周期等信号轴发生了异常。这一发现很重要，因为它揭示了小鼠狼疮的一些良好的治疗靶点。在完成的工作中，我们已经证明阻断AKT/mTOR激活可以治疗小鼠狼疮。最近，我也证明了MAPK和NF-:B活化也是很好的治疗靶点，使用CDDO-me和nemo结合肽作为治疗剂（手稿正在准备中）。最后，我最近定义了几种在小鼠狼疮中也上调的t细胞信号通路（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全kinome测定结果，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，该功能筛选证实了我们使用western blots发表的一些数据。此外，这项全面的kinome筛选还揭示了一些新的重要的信号分子，这些信号分子可能在指导狼疮的发病中具有重要的作用。总的来说，这些研究表明信号分子可能是狼疮的良好治疗靶点。这项拨款的目的是将这些发现转化为人类SLE。在这项研究中，我们有两个具体的目标。目的1：研究Aurora A， Plk1， PKR， RSK3和RIPK3在小鼠狼疮白细胞中的表达，根据我们最近全面的kinome筛选结果进行推断。目的2：利用“逆相信号阵列”综合筛选平台，研究SLE患者白细胞内选定的信号轴（已确定在狼疮小鼠中升高）的表达。

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. .