Genomic and nongenomic cortisol signaling in fish

压力是生活的一部分。对压力的一种急性反应是产生皮质类固醇，这在所有被研究的脊椎动物中都可以看到。大多数脊椎动物在应激反应中产生的主要皮质类固醇是皮质醇。这种类固醇激素的刺激带来了一些分子、生化和生理上的变化，这与这种激素在应激适应中所起的重要作用是一致的。然而，应激源暴露与这种高度保守的类固醇反应的益处之间的因果关系仍然缺乏。这是因为我们对这种类固醇在使动物应对压力方面的作用方式知之甚少。皮质醇的作用涉及两个关键蛋白，糖皮质激素受体（GR）和矿皮质激素受体（MR），它们传递导致基因表达变化的信息（基因组信号传导）。最近的研究表明，皮质醇的另一种作用模式导致了快速的效果，但独立于GR和MR激活（非基因组信号）。然而，其机制还远不清楚。本提案旨在描述这些皮质醇信号通路在皮质类固醇生产发展中的作用，以及应激应对机制。以斑马鱼和虹鳟鱼为研究对象，通过基因敲低和药理学方法，建立二者响应皮质醇信号的因果关系。具体来说，本研究将利用基因组和磷蛋白质组学分析，确定受受体依赖和受体独立方式的皮质醇信号调节的基因和蛋白质网络。总体目标是发现涉及皮质醇信号传导的新途径，并将建立类固醇分泌和应激适应之间的机制联系。

Stress is part and parcel of life. One of the acute responses to stress is the production of corticosteroids and this is seen in all vertebrates studied. The predominant corticosteroid produced in response to stress in most vertebrates is cortisol. The stimulation by this steroid hormone brings about several molecular, biochemical and physiological changes, and is consistent with the important role this hormone is thought to play in stress adaptation. However, a cause and effect relationship between stressor exposure and the benefits of this highly conserved steroid response is still lacking. This is because we know so little about the mode of action of this steroid in allowing animals to cope with stress. Cortisol action involves two key proteins, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), which relay information that results in gene expression changes (genomic signaling). Recent studies suggest yet another mode of action of cortisol that results in rapid effects, but independent of GR and MR activation (nongenomic signaling). However, the mechanisms are far from clear. This proposal intends to describe the role of these cortisol signaling pathways in the development of corticosteroid production, and stress coping mechanisms. Using zebrafish and rainbow trout, a cause and effect relationship in response to cortisol signaling will be established by using gene knockdown and pharmacological methods. Specifically, using genome and phosphoproteome analyses, this study will identify the regulatory gene and protein networks modified by cortisol signaling in a receptor-dependent and receptor-independent fashion. The overall goal is to discover novel pathways involved in cortisol signaling and will establish a mechanistic link between this steroid secretion and stress adaptation.