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和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特定环境压力反应的机制。在应激反应的效应器中，关键的是促肾上腺皮质激素释放因子（CRF）和皮质醇，它们分别是主要的中枢调节剂和神经内分泌应激轴的终产物。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对鱼类的环境应激具有细胞保护作用，包括神经保护作用，现在试图确定CRF预防神经变性和促进神经再生的具体机制。第二，我们确定了CRF系统的组成部分在鱼的鳃和肠中表达，并表明这些对盐度的变化有反应，这促使进一步研究CRF系统的调节功能。最后，我们发现，长期暴露于环境压力增加了母亲到后代的热休克蛋白，介导的细胞应激反应，并减少鸡蛋皮质醇含量，其功能的后果是未知的。因此，拟议的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系统对视网膜调节功能的贡献;（3）确定暴露于母体环境应激源如何影响后代的应激耐受性。为了实现这些目标，我们将使用一套全面的技术，从整个动物到分子水平，并选择非常适合手头问题的研究模型。所要求的资金将使我能够培训至少3名博士，3名硕士和10名理科学生，他们将获得先进和多样化的技术技能，这些技能对不同的科学职业非常宝贵。我们的研究预计将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的理解的机制参与维持视网膜的完整性，扩展我们的理解CRF系统的进化保守的功能，通过提供第一个机械洞察CRF的神经调节功能，并提供基本的洞察力的机制，其中遇到的压力在父母一代程序后代压力耐受性。

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.