Expression and Function of SOCS Proteins in Glial Cells

SOCS 蛋白在胶质细胞中的表达和功能

• 批准号: 7769836
• 负责人: Etty N Benveniste
• 金额: $ 25.12万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769836
• 关键词: AIDS Dementia Complex; Acute; Affect; Alzheimer' s Disease; Antigen Presentation; Astrocytes; Attenuated; Binding; Biological; Biological Process; CXCL10 gene; Cell Line; Cell Nucleus; Cell Surface Receptors; Cell physiology; Cells; Central Nervous System Diseases; Chronic; Cognitive; Cytokine Inducible SH2-Containing Protein; Cytokine Receptors; Cytoplasmic Tail; Defense Mechanisms; Disease; Docking; Elements; Emotional; Event; Family; Family member; Feedback; Future; Gene Expression; Genes; Genetic Transcription; Goals; Immune; Immune response; Infiltration; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-6; JAK1 gene; JAK2 gene; JAK3 gene; Janus kinase; Lipopolysaccharides; MHC class II transactivator protein; Macrophage Activation; Mediating; Membrane; Microglia; Molecular; Multiple Sclerosis; Mus; Nervous System Physiology; Neuraxis; Neuroglia; Neurons; Pathology; Pathway interactions; Phosphorylation; Process; Production; Protein Tyrosine Kinase; Proteins; Regulation; STAT protein; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Site; Small Interfering RNA; Stimulus; Synaptic plasticity; TNFRSF5 gene; TYK2; Transcriptional Activation; Tyrosine; autocrine; base; cell type; chemokine; cytokine; macrophage; neurogenesis; neuropathology; neurotoxic; neurotoxicity; oncostatin M; paracrine; programs; protein function; receptor; response; restoration

DESCRIPTION (provided by applicant): Our goal is to understand the basis of immune and inflammatory responses within the CNS. Immunological activation of macrophages/microglia and astrocytes leads to the production of cytokines that impact on glial and neuronal function. Cytokines have far-reaching effects in the CNS, including the initiation and regulation of immune/inflammatory responses. Macrophages/microglia and astrocytes not only produce cytokines, but also respond to them via cell surface receptors. Macrophage/microglial and astrocytic activation in general is aimed at promoting a beneficial restoration of endangered CNS elements and functions. However, excessive and sustained stimulation of these cells contributes to acute and chronic neuropathologies. Therefore, dysregulation of macrophage/microglial and astrocytic cytokine production and responsiveness may promote direct neurotoxicity, as well as disturb neural cell functions. The biological effects of cytokines are mediated by intracellular signal transduction pathways; the most common being the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway (JAK-STAT). Cytokines implicated in CNS pathology include IFN-y, IFN-p and IL-6 family members, all of which signal through the JAK-STAT pathway. A precise regulation of both the magnitude and duration of JAK and STAT activation is essential, as dysregulation of the JAK-STAT pathway has pathological implications. Suppressors of Cytokine Signaling (SOCS) proteins function to inhibit the JAK-STAT pathway. SOCS proteins are inducible by cytokines, and inhibit signaling by directly binding to cytokine receptor chains or associated JAKs to inhibit tyrosine kinase activity, thereby functioning in a negative feedback loop. There is limited information regarding the expression and function of SOCS proteins within the CNS. Our preliminary results indicate that both SOCS-1 and SOCS-3 function to attenuate expression of genes critical for immune/inflammatory responses in macrophages/microglia and astrocytes. We hypothesize that expression of SOCS-1/SOCS-3 will attenuate cytokine-induced inflammatory and immune responses by inhibiting activation of these cells, thereby exerting beneficial effects for immune-mediated CNS diseases. We will examine the ability of astrocytes, microglia and macrophages to express SOCS-1/SOCS-3 proteins in response to CNS-relevant stimuli, and elucidate the transcriptional programs underlying SOCS-1/SOCS-3 gene transcription (Aims 1 and 3). The ability of SOCS-1/SOCS-3 to modulate immunological and inflammatory responses in glial cells and macrophages will also be examined (Aims 2 and 4), using macrophage and astroglial cell lines that express siRNA against SOCS-1/SOCS-3 in an inducible manner. Our proposed studies will provide the first biological assessment of SOCS-1/SOCS-3 production and function in cells of the CNS, thereby providing the basis for future assessment of SOCS-1/SOCS-3 as attenuators of inflammatory and neurotoxic responses in the CNS.

描述（由申请人提供）：我们的目标是了解中枢神经系统内免疫和炎症反应的基础。巨噬细胞/小胶质细胞和星形胶质细胞的免疫激活导致细胞因子的产生，影响胶质和神经元的功能。细胞因子在中枢神经系统中具有深远的影响，包括免疫/炎症反应的启动和调节。巨噬细胞/小胶质细胞和星形胶质细胞不仅产生