Analysis of adaptive responses of astrocytes

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。

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.