Glucocorticoid receptor phosphorylation in endocrine adaptation to stress

项目摘要 糖皮质激素在中枢神经系统中发挥许多作用，从空间学习和认知， 压力和抑郁有趣的是，糖皮质激素对神经元回路的影响也很强烈。 受神经营养因子的影响，如脑源性神经营养因子（BDNF）。我们发现了一本小说 糖皮质激素和BDNF之间的通讯途径，使BDNF信号增加GR 在丝氨酸155（S155）和287（S287）处的磷酸化。这改变了由GR控制的基因库， GR磷酸化位点的破坏损害了慢性应激时的神经可塑性。这个目标 我们的建议是了解GR在S155和S287磷酸化的生理相关性， 利用新开发的GR磷酸化位点缺陷的神经内分泌适应体内应激 （S155A/S287A）基因敲入小鼠，以及参与磷酸化依赖性 调节GR介导的基因表达。我们的方法包括分子，成像和行为 研究，GR靶基因和受体占有率的全基因组评估，以及突触 在独特的GR S155A/S287A基因敲入小鼠模型中使用双光子显微镜观察应激后的可塑性。 我们还将检测抑郁症患者与非抑郁症患者的PBMC中GR pS155/pS287是否发生改变。 让这条途径与人类行为相关。我们的研究将阐明基因组网络 GR pS155/pS287通过其控制神经内分泌对应激的适应。

Project Summary Glucocorticoids exert many effects in the central nervous system ranging from spatial learning and cognition to stress and depression. Interestingly, the effects of glucocorticoids upon neuronal circuits are also strongly influenced by neurotrophins, such as Brain Derived Neurotrophic Factor (BDNF). We have identified a novel pathway of communication between glucocorticoids and BDNF such that BDNF-signaling increased GR phosphorylation at serines 155 (S155) and 287 (S287). This altered the repertoire of genes controlled by GR, and disruption of the GR phosphorylation sites impaired neuroplasticity upon chronic stress. The goal of this proposal is to understand the physiological relevance of GR phosphorylation at S155 and S287 in neuroendocrine adaptation to stress in vivo using a newly developed GR phosphorylation-site-deficient (S155A/S287A) knock-in mouse, as well as the molecular mechanisms involved in phosphorylation-dependent regulation of GR-mediated gene expression. Our approaches include molecular, imaging and behavioral studies, genome wide assessment of GR target genes and receptor occupancy, as well as analysis of synaptic plasticity upon stress using two photon microscopy in the unique GR S155A/S287A knock-in mouse model. We will also examine whether GR pS155/pS287 is altered in PBMCs of depressed versus not depressed humans to lend relevance of this pathway to human behavior. Our studies will illuminate the genomic networks by which GR pS155/pS287 controls neuroendocrine adaptation to stress.