Regulation and function of the stress response in fish

应激反应在面对不利力量时维持最佳身体平衡方面起着至关重要的作用，但我们对调节这种适应性生理反应的复杂而相互关联的神经内分泌、细胞和分子途径知之甚少。因此，我的研究计划的长期目标是了解负责特定环境应激反应的机制。应激反应的关键效应因子是促肾上腺皮质激素释放因子（CRF）和皮质醇，它们分别是神经内分泌应激轴的主要中枢调节因子和最终产物。因此，确定CRF和皮质醇的新作用，并确定它们与维持体内平衡的生理相关性也是我研究计划的持续目标。我们最近在三个方面的研究进展构成了这一建议的基础。首先，我们发现CRF对鱼类的环境应激源具有细胞保护作用，包括神经保护作用，现在我们试图确定CRF预防神经变性和促进神经再生的具体机制。其次，我们确定了CRF系统的组成部分在鱼类的鳃和肠道中表达，并表明这些部分对盐度的变化有响应，这促使了对CRF系统渗透调节功能的进一步研究。最后，我们发现，长期暴露于环境应激源会增加热休克蛋白（细胞应激反应的介质）在母体向后代的传递，并降低卵子皮质醇含量，其功能后果尚不清楚。因此，该研究将解决三个短期目标：(1)确定视网膜CRF系统具有细胞保护作用的机制；(2)确定鳃和肠道CRF系统对渗透调节功能的贡献；(3)确定母源环境应激对子代应激耐受性的影响。为了实现这些目标，我们将使用从整个动物到分子水平的综合技术套件，并选择最适合手头问题的研究模型。申请的资金将允许我培养至少3名博士，3名硕士和10名理学士学生，他们将获得先进和多样化的技术技能，这对不同的科学事业是无价的。我们的研究有望对我们对鱼类如何进化出应对环境压力的解决方案的基本理解产生广泛的影响。具体来说，我们的研究将影响我们对维持视网膜完整性机制的理解，通过提供CRF渗透调节功能的第一个机制见解，扩展我们对CRF系统进化保守功能的理解，并为亲代程序中遇到的应激源的机制提供基本见解。

The stress response plays an essential role in maintaining the optimal body equilibrium in the face of adverse forces, but we know relatively little about the intricate and interconnected neuroendocrine, cellular, and molecular pathways that regulate this adaptive physiological response. Therefore, the long-term objective of my research program is to understand the mechanisms responsible for context-specific stress responses. Key among the effectors of the stress response is corticotropin-releasing factor (CRF) and cortisol, the principle central regulator and the end-product of the neuroendocrine stress axis, respectively. As such, identifying novel actions of CRF and cortisol, and determining their physiological relevance for maintaining homeostasis are also ongoing objectives of my research program. Our recent research advances on three fronts form the basis of this proposal. First, we identified that CRF has cytoprotective effects against environmental stressors in fish, including neuroprotective actions, and now seek to identify the specific mechanisms by which CRF prevents neurodegeneration and promote neuro-regeneration. Second, we determined that components of the CRF system are expressed in the gills and intestine of fish and showed that these are responsive to changes in salinity, prompting further research into the osmoregulatory functions of the CRF system. Lastly, we discovered that chronic exposure to environmental stressors increases the maternal-to-offspring transfer of heat shock proteins, mediators of the cellular stress response, and a reduction in egg cortisol content, the functional consequences of which are unknown. Therefore, the proposed research will address three short-term objectives: (1) determine the mechanisms by which the retinal CRF system is cytoprotective; (2) identify the contributions of the gill and intestinal CRF systems to osmoregulatory functions; and (3) determine how exposure to maternal environmental stressors impacts offspring stress tolerance. To address these objectives, we will use a comprehensive suite of techniques ranging from the whole animal to the molecular levels and select research models ideally suited for the question at hand. The funding requested will allow me to train at least 3 PhD, 3 MSc, and 10 BSc students, who will obtain advance and diverse technical skills that are invaluable for diverse scientific careers. Our research is expected to have a broad impact on our fundamental understanding of how fish have evolved solutions to handle environmental stressors. Specifically, our research will impact our understanding of the mechanisms involved in maintaining retinal integrity, extend our understanding of the evolutionary-conserved functions of the CRF system by providing the first mechanistic insight into the osmoregulatory functions of CRF, and offer fundamental insights into the mechanisms by which stressors encountered in the parental generation program progeny stress tolerance.