Signaling Status in Lupus
狼疮的信号状态
基本信息
- 批准号:8099042
- 负责人:
- 金额:$ 7.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAutoimmune DiseasesB-LymphocytesBindingBiochemicalBiological AssayBrainCell CycleCellsComplexDataDevelopmentDiseaseFamily memberGenesGeneticGoalsGrantHLA-DR AntigensHumanIRAK1 geneImmuneImmune responseImmune systemJointsKidneyLYN geneLaboratoriesLeukocytesLupusLymphocyteMAP Kinase GeneMAP2K1 geneMAPK11 geneManuscriptsMolecularMorbidity - disease rateMusMyeloid CellsOrganPI3K/AKTPTPN22 genePathogenesisPatientsPeptidesPhasePhosphotransferasesPreparationProteomicsProto-Oncogene Proteins c-aktPublishingRIPK3 geneSTAT4 geneScreening procedureSignal PathwaySignal TransductionSignaling MoleculeSkinSystemic Lupus ErythematosusT-Cell ActivationT-LymphocyteTherapeuticTimeTranslatingWestern BlottingWorkbasefunctional statushuman FRAP1 proteinhuman STK6 proteininterestmortalitymouse modelnovelpublic health relevancetherapeutic target
项目摘要
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. .
描述(由申请人提供): 狼疮是一种复杂的自身免疫性疾病,具有显著的发病率和死亡率,其中异常的免疫系统引起影响关节、脑、皮肤和肾脏的器官损伤。然而,狼疮发病机制的分子机制在很大程度上是未知的。以往的研究表明,免疫细胞,如B细胞,T细胞和髓系细胞在狼疮是过度增殖和过度活跃的疾病。近年来的遗传学研究发现了许多重要的狼疮相关基因,包括先天免疫相关基因如IRF 5、STAT 4和IRAK 1等,B细胞信号传导相关基因如BLK、BANK 1、林恩和Ly 108等;与T细胞活化相关的基因如PTPN 22、HLA-DR、PDCD 1等,同时发现了PI 3 K/AKT/mTOR、MEK 1/Erk 1/2、p38、NF-:B、多个Bcl-2家族成员和细胞周期在狼疮小鼠模型的淋巴细胞中与正常对照相比是异常的。这一发现很重要,因为它揭示了小鼠狼疮中一些良好的治疗靶点。在完成的工作中,我们已经表明,阻断AKT/mTOR激活可以治疗小鼠狼疮。最近,我还表明,MAPK和NF-:B激活也是很好的治疗目标,使用CDDO-me和NEMO结合肽作为治疗剂(手稿准备)。最后,我最近定义了几个在鼠狼疮中也上调的T细胞信号通路(手稿在准备中)。提出这项研究的另一个重要原因是基于我们最近的全激酶组测定结果,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蛋白质印迹法发表的一些数据。此外,这种全面的激酶组筛选还揭示了一些新的和重要的信号分子,这些分子可能在引导狼疮发展中具有致病重要性。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。该基金的目标是将这些发现转化为人类SLE。在这项研究中,我们有两个具体目标。目标1:研究Aurora A、Plk 1、PKR、RSK 3和RIPK 3在小鼠狼疮白细胞中的表达,并从我们最近的综合激酶组筛选结果中推断。目标二:使用“反相信号阵列”(一种综合筛选平台)研究SLE患者白细胞内选定信号轴(已确定在小鼠狼疮中升高)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发现一些信号分子,特别是激酶在狼疮小鼠中上调。在这项研究中,我们将通过使用新的生物化学和蛋白质组学方法来验证这些潜在的有趣分子,以绘制可能有助于狼疮发展的信号网络。.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Tianfu Wu其他文献
Tianfu Wu的其他文献
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{{ truncateString('Tianfu Wu', 18)}}的其他基金
A biomarker panel based smart mini-array system for the homecare of autoimmune kidney diseases
基于生物标记物面板的智能微型阵列系统,用于自身免疫性肾病的家庭护理
- 批准号:
9900712 - 财政年份:2019
- 资助金额:
$ 7.61万 - 项目类别:
A biomarker panel based smart mini-array system for the homecare of autoimmune kidney diseases
基于生物标记物面板的智能微型阵列系统,用于自身免疫性肾病的家庭护理
- 批准号:
10092890 - 财政年份:2019
- 资助金额:
$ 7.61万 - 项目类别:
A biomarker panel based smart mini-array system for the homecare of autoimmune kidney diseases
基于生物标记物面板的智能微型阵列系统,用于自身免疫性肾病的家庭护理
- 批准号:
10555290 - 财政年份:2019
- 资助金额:
$ 7.61万 - 项目类别:
A biomarker panel based smart mini-array system for the homecare of autoimmune kidney diseases
基于生物标记物面板的智能微型阵列系统,用于自身免疫性肾病的家庭护理
- 批准号:
10337193 - 财政年份:2019
- 资助金额:
$ 7.61万 - 项目类别:
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