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: 7313365
• 负责人: Etty N Benveniste
• 金额: $ 25.38万
• 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/7313365
• 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学激活导致影响对神经胶质和神经元功能的细胞因子的产生。细胞因子在中枢神经系统中具有深远的影响，包括免疫/炎症反应的起始和调节。巨噬细胞/小胶质细胞和星形胶质细胞不仅产生 细胞因子，但也通过细胞表面受体反应。巨噬细胞/小胶质细胞和星形细胞激活通常旨在促进濒危CNS元素和功能的有益恢复。然而，这些细胞的过度和持续刺激有助于急性和慢性神经病理学。因此，巨噬细胞/小胶质细胞和星形细胞因子的产生和反应性的失调可能促进直接的神经毒性，并干扰神经细胞功能。细胞因子的生物学作用是由细胞内信号转导途径介导的。最常见的是Janus激酶（JAK）和信号换能器以及转录（Stat）途径（JAK-STAT）的激活因子。与CNS病理学有关的细胞因子包括IFN-Y，IFN-P和IL-6家族成员，所有这些都通过JAK-Stat途径发出信号。对JAK的大小和持续时间和Stat激活的持续时间的精确调节至关重要，因为JAK-Stat途径的失调具有病理意义。细胞因子信号传导（SOCS）蛋白的抑制器功能抑制JAK-StAT途径。 SOCS蛋白可通过细胞因子诱导，并通过直接与细胞因子受体链或相关JAKS结合以抑制酪氨酸激酶活性，从而抑制信号传导，从而在负反馈环中发挥作用。 关于SOCS蛋白质的表达和功能的信息有限 CNS。我们的初步结果表明，SOCS-1和SOCS-3的功能都可以减弱巨噬细胞/小胶质细胞和星形胶质细胞中免疫/炎症反应至关重要的基因的表达。我们假设SOCS-1/SOCS-3的表达将通过抑制这些细胞的激活来减轻细胞因子诱导的炎症和免疫反应，从而对免疫介导的CNS疾病产生有益的作用。我们将研究星形胶质细胞，小胶质细胞和巨噬细胞以响应与CNS相关的刺激，表达SOCS-1/SOCS-3蛋白的能力，并阐明SOCS-1/SOCS-1/SOCS-3基因转录的转录程序（AIMS 1和3）。还将检查SOCS-1/SOCS-3在神经胶质细胞和巨噬细胞中调节免疫学和炎症反应的能力（AIMS 2和4），使用巨噬细胞和星形胶质细胞系以可诱导的方式表达siRNA针对SOCS-1/SOCS-3。我们提出的研究将提供CNS细胞中SOCS-1/SOCS-3产生和功能的首次生物学评估，从而为将来评估SOCS-1/SOCS-3作为CNS炎症和神经毒性反应的衰减者提供了基础。