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Analysis of adaptive responses of astrocytes

星形胶质细胞的适应性反应分析

基本信息

批准号：
9277132
负责人：
TOMASZ K KORDULA
金额：
$ 19.06万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277132
关键词：
Affect Astrocytes Blood - brain barrier anatomy Brain Cells Cytokine Activation Cytokine Gene Data Deacetylase Deacetylation Development Disease Outcome Disease Progression Disease model Endotoxins Epigenetic Process Excision Experimental Autoimmune Encephalomyelitis Family Gene Expression Genes Hallmark Cell Heterogeneity Human IRF1 gene Immune Infection Infiltration Inflammation Inflammation Mediators Inflammatory Response Interferons Interleukin-1 Ischemia Knockout Mice LCN2 gene Lead Lysine Memory Metabolic Metabolism Microglia Molecular Molecular Profiling Morphology Nerve Degeneration Neurons Outcome Pathologic Processes Phosphorylation Physiological Play Process Production Publishing Recruitment Activity Role SIRT1 gene STAT protein STAT1 gene Signal Transduction Specificity Stimulus TNF gene TNFRSF5 gene Testing Transferase Traumatic Brain Injury astrogliosis base cytokine experimental study extracellular histone methylation imprint in vivo inhibitor/antagonist knock-down macrophage member monocyte neuroinflammation novel programs response synaptogenesis transcriptome sequencing

项目摘要

Reactive astrogliosis is associated with brain trauma, infections, ischemia, and neurodegeneration. As astrocytes become reactive, they undergo dramatic morphological and functional changes and both secrete and respond to a host of inflammatory mediators. We asked the question whether astrocytes also display adaptive plasticity of their responses, including priming and tolerance. In preliminary studies, we established that primary human astrocytes develop both “cytokine-tolerance” that depends on induction of RelB expression, its phosphorylation on Ser472, recruitment of the deacetylase SIRT1 and the lysine methyl transferase KMT1C and subsequent epigenetic silencing of cytokine genes. Surprisingly, we have also identified a set of intriguing and novel RelB-induced genes, which can be “primed” likely by an IRF1- and STAT1-dependent mechanism. We propose to test the hypothesis that cytokine- induced RelB drives gene expression programs regulating astrocyte adaptive responses and thus disease outcomes. We will 1) define the molecular basis of “cytokine-tolerance” and “priming” in astrocytes, and 2) d etermine the role of RelB in astrocyte activation in vivo.

反应性星形胶质细胞增生症与脑外伤、感染、缺血和神经变性当星形胶质细胞变得具有反应性时，它们经历了戏剧性的形态学变化，功能变化，并且两者都分泌并响应于大量炎症介质。我们问问题是星形胶质细胞是否也表现出其反应的适应性可塑性，包括启动和耐受性。在初步研究中，我们确定了原代人类星形胶质细胞发展依赖于诱导RelB表达的“耐药性”，丝氨酸472上的磷酸化，脱乙酰酶SIRT 1和赖氨酸甲基化的募集，转移酶KMT 1C和随后的细胞因子基因的表观遗传沉默。令人惊讶的是，还发现了一组有趣的和新的RelB诱导基因，这些基因可能是由 IRF 1和STAT 1依赖性机制。我们打算检验细胞因子- 诱导的RelB驱动调节星形胶质细胞适应性反应的基因表达程序，疾病结果。我们将1）定义“抗胆碱”和“引发”的分子基础，星形胶质细胞，和2）d 确定RelB在体内星形胶质细胞活化中的作用。