Glucocorticoid receptor phosphorylation in endocrine adaptation to stress

糖皮质激素受体磷酸化在内分泌适应应激中的作用

• 批准号: 9883840
• 负责人: Michael J. Garabedian
• 金额: $ 49.54万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883840
• 关键词: Address; Adult; Affect; Anxiety; Architecture; Behavior; Binding; Bioinformatics; Brain; Brain-Derived Neurotrophic Factor; CRISPR interference; Cerebral cortex; ChIP-seq; Chronic stress; Cognition; Communication; Complex; DNA; Defect; Dendritic Spines; Depressed mood; Endocrine; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Hormones; Human; Immunoprecipitation; Impairment; In Vitro; Intervention; Knock-in; Knock-in Mouse; Learning; Ligands; Link; Locomotion; Major Depressive Disorder; Mass Spectrum Analysis; Mediating; Memory; Mental Depression; Molecular; Molecular Conformation; Morphology; Mus; Mutation; Neuraxis; Neuronal Plasticity; Neurons; Neurosecretory Systems; Neurotrophic Tyrosine Kinase Receptor Type 2; Nuclear Proteins; Pathway interactions; Peripheral Blood Mononuclear Cell; Phosphorylation; Phosphorylation Site; Physiological; Physiology; Play; Production; Proteomics; Regulation; Regulatory Element; Risk Factors; Role; Serine; Signal Pathway; Signal Transduction; Site; Specific qualifier value; Stress; Synaptic plasticity; Testing; Treatment Factor; behavioral response; behavioral study; biological adaptation to stress; cell type; density; design; disability; gene product; genetic regulatory protein; genome-wide; glucocorticoid receptor alpha; hypothalamic-pituitary-adrenal axis; imaging study; in vivo; induced pluripotent stem cell; insight; loss of function; molecular imaging; mouse model; mutant; neuronal circuitry; neuroprotection; neuropsychiatric disorder; neurotrophic factor; novel; overexpression; receptor; recruit; resilience; response; transcription factor; transcriptome; transcriptome sequencing; two photon microscopy

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.

项目摘要 糖皮质激素在中枢神经系统中发挥许多作用，从空间学习和认知到 压力和沮丧。有趣的是，糖皮质激素对神经元电路的影响也很强 受神经营养蛋白的影响，例如脑衍生的神经营养因子（BDNF）。我们已经确定了一本小说 糖皮质激素与BDNF之间的通信途径使得bdnf信号增加了GR 丝氨酸155（S155）和287（S287）处的磷酸化。这改变了由GR控制的基因的曲目 GR磷酸化位点的破坏会在慢性应激下损害神经可塑性。目标的目标 建议是了解S155和S287的GR磷酸化的生理相关性 神经内分泌适应对体内胁迫的适应性，使用新开发的GR磷酸化位点缺陷 （S155A/S287A）敲入小鼠，以及与磷酸化有关的分子机制 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靶基因和受体占用率的基因组广泛评估，以及突触的分析 在独特的GR S155A/S287A敲入小鼠模型中，使用两个光子显微镜在应力时进行塑性。 我们还将检查GR PS155/PS287是否在抑郁症与不抑郁的PBMC中发生了变化 人类将这种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控制着神经内分泌对应激的适应性。

项目成果

Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks.

• DOI: 10.1080/10253890.2020.1806226
• 发表时间: 2021-03
• 期刊: Stress (Amsterdam, Netherlands)
• 作者: Huzard D;Rappeneau V;Meijer OC;Touma C;Arango-Lievano M;Garabedian MJ;Jeanneteau F
• 通讯作者: Jeanneteau F