TRADD as a Regulator of Cytokine Signaling in Glia

TRADD 作为神经胶质细胞因子信号传导的调节剂

• 批准号: 7455118
• 负责人: Etty N Benveniste
• 金额: $ 28.71万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-19 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455118
• 关键词: AIDS Dementia Complex; Acute; Adaptor Signaling Protein; Address; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Astrocytes; Binding; Biological; Brain; Cell Nucleus; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Chronic; Cognitive; Communication; Complex; Cytokine Signaling; DNA Binding; Data; Death Domain; Defense Mechanisms; Dimerization; Disease; Elements; Emotional; Endothelial Cells; Epidermal Growth Factor; Event; Family member; Gene Expression; Genes; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferons; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-4; Interleukin-6; Ischemia; Lead; Localized; Macrophage Activation; Mediating; Microglia; Molecular; Multiple Sclerosis; Nature; Neuraxis; Neuroglia; Neurons; Nuclear; Nuclear Protein; Nuclear Proteins; Nuclear Translocation; Numbers; PTPN11 gene; Pathology; Pathway interactions; Personal Satisfaction; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Play; Process; Production; Protein Dephosphorylation; Protein Overexpression; Protein Tyrosine Phosphatase; Proteins; Receptor Activation; Recruitment Activity; Regulation; Research; Research Personnel; Role; STAT protein; Series; Serine; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Site; Source; Stimulus; Synaptic plasticity; Testing; Tumor Necrosis Factor Receptor; Tyrosine; Tyrosine Phosphorylation; Virus Diseases; base; cell growth; cell type; chemokine; concept; cytokine; interest; macrophage; neurogenesis; neuroinflammation; neuropathology; neurotoxicity; novel; oncostatin M; paracrine; programs; promoter; protein protein interaction; receptor; reconstitution; research study; response; restoration; scaffold; transcription factor

DESCRIPTION (provided by applicant): Inflammatory events in the Central Nervous System (CNS) contribute to the pathology underlying diseases such as Multiple Sclerosis (MS), Alzheimer's Disease (AD) and HIV-1 Associated Dementia (HAD), and activated macrophages/microglia are central to this response. Immunological activation of these cells leads to the production of cytokines that ultimately impact on glial and neuronal function. Macrophages/microglia also respond to cytokines upon engagement of cell surface receptors and activation of complex intracellular signaling pathways. Dysregulation of macrophage/microglial cytokine production and responsiveness is a critical determinant of the neuroimmunologic cascades that typify diseases such as MS, AD and HAD. IFN- and TNF-a are potent activators of macrophages and microglia, and are aberrantly expressed in the CNS in the diseases mentioned above. IFN-y uses Signal Transducer and Activator of Transcription-la (STAT-la) for signal transduction, while the Tumor Necrosis Factor Receptor 1 (TNFRl)-associated death domain (TRADD) protein is critical for TNF-a signaling. We have discovered a novel and unanticipated form of crosstalk between the IFN? and TNF-a signaling pathways that is operational in macrophages/microglia. Specifically, we have demonstrated that IFN-? induces the formation of a nuclear-localized TRADD-STAT-la complex. In this configuration, we propose that TRADD is involved in the dephosphorylation of STAT-la since IFN-?-induced STAT-la phosphorylation, DNA binding activity, nuclear retention and transcriptional activity are enhanced in cells with reduced TRADD levels. We hypothesize that TRADD has a functional role in regulating the response of macrophages/microglia to IFN-?, impacting on cellular activation and subsequent neuroinflammatory responses. The function of TRADD on IFN-?-induced gene expression in macrophages/microglia will be studied, focusing on genes critical for immunological responses (Aim 1). Two strategies are proposed: depletion of TRADD as well as TRADD reconstitution and/or overexpression. In Aim 2, we will test the hypothesis that TRADD is involved in the STAT-la dephosphorylation process, perhaps by interacting with STAT-la phosphatases to regulate their localization and/or activity. A critical issue is how signaling from the IFN-? receptor induces nuclear localization of TRADD, and subsequent TRADD-STAT-la complex formation. The experiments in Aim 3 will address these questions. Lastly, we will examine the ability of other cytokines that use the STAT pathway to induce TRADD-STAT complex formation, and the repertoire of cell types in which TRADD-STAT interactions occur (Aim 4). Our studies will provide a comprehensive assessment of TRADD function in cytokine signaling, thereby advancing our understanding of this novel signaling pathway in the context of macrophage/microglial activation and neuroinflammation.

描述（由申请人提供）：中枢神经系统中的炎症事件（CNS）有助于诸如多发性硬化症（MS），阿尔茨海默氏病（AD）和HIV-1相关痴呆症（HAS）以及激活的巨噬细胞/小胶质细胞等病理的核心。这些细胞的免疫学激活导致产生最终影响神经胶质和神经元功能的细胞因子。巨噬细胞/小胶质细胞还会在细胞表面受体接合并激活复杂细胞内信号通路后对细胞因子反应。巨噬细胞/小胶质细胞因子的产生和反应性的失调是典型的MS，AD和HAT等疾病的神经免疫性级联反应的关键决定因素。 IFN和TNF-A是巨噬细胞和小胶质细胞的有效活化剂，并且在上述疾病中的中枢神经系统中异常表达。 IFN-Y使用转录-LA（Stat-LA）的信号传感器和激活因子进行信号转导，而肿瘤坏死因子受体1（TNFRL）相关的死亡结构域（TRADD）蛋白对于TNF-A信号传导至关重要。我们在IFN之间发现了一种新颖而意外的串扰形式？在巨噬细胞/小胶质细胞中运行的TNF-A信号通路。具体来说，我们已经证明了IFN-？诱导核定位的Tradd-STAT-LA复合体的形成。在这种配置中，我们建议传统参与Stat-LA的去磷酸化，因为IFN - ？ - 诱导的STAT-LA磷酸化，DNA结合活性，核保留和转录活性在降低的Tradd水平的细胞中增强了。我们假设TRADD在调节巨噬细胞/小胶质细胞对IFN-的反应中具有功能性作用，从而影响细胞激活和随后的神经炎症反应。将研究传统对巨噬细胞/小胶质细胞中诱导基因表达的功能，重点是对免疫反应至关重要的基因（AIM 1）。提出了两种策略：Tradd的耗尽以及Tradd重建和/或过表达。在AIM 2中，我们将通过与Stat-La磷酸酶相互作用以调节其定位和/或活动的相互作用来检验TRADD参与Stat-LA去磷酸化过程的假设。一个关键的问题是如何发出IFN-的信号？受体诱导传统的核定位，并随后的传统-STAT-LA复合体形成。 AIM 3中的实验将解决这些问题。最后，我们将研究使用统计途径诱导传统stat复合形成的其他细胞因子的能力，以及发生传统相互作用的细胞类型的曲目（AIM 4）。我们的研究将对细胞因子信号传导中传统功能进行全面评估，从而在巨噬细胞/小胶质细胞激活和神经炎症的背景下促进我们对这一新型信号通路的理解。