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多种作用，从空间学习和认知到 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。 受神经营养因子影响，如脑源性神经营养因子(BDNF)。我们已经确定了一部小说 糖皮质激素与脑源性神经营养因子之间的信息传递途径 丝氨酸155(S155)和287(S287)的磷酸化。这改变了GR控制的基因谱系， 慢性应激时GR磷酸化位点的破坏会损害神经的可塑性。这样做的目的是 建议了解S155和S287处GR磷酸化的生理相关性 利用新发现的GR磷酸化位点缺陷基因实现体内神经内分泌对应激的适应 (S155A/S287A)敲入小鼠及其磷酸化依赖的分子机制 GR介导的基因表达的调控。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，以及突触分析 在独特的GR S155A/S287A敲入小鼠模型中，使用双光子显微镜研究应力下的可塑性。 我们还将研究抑郁症与非抑郁症患者外周血单核细胞中GR pS155/pS287是否发生改变 人类将这一途径与人类行为相关联。我们的研究将阐明基因组网络 GR pS155/pS287通过其调控神经内分泌对应激的适应性。

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.