Cortisol stress axis development and function in fish

我的研究计划旨在发现新的细胞信号和应激类固醇皮质醇调制的转导途径，并推进我们对这些反应如何在整个动物水平上整合以驱动功能的基本知识。我这个5年计划的短期目标是解决母体皮质醇在规划后代压力轴功能发展中所起的作用。最重要的假设是，母体压力和相关的增加皮质醇沉积到胚胎将减少皮质醇清除机制孵化前，并会导致后代皮质类固醇应激轴性能的功能障碍。三个具体的概念正在解决：i）是母亲转移皮质醇绝对必要的斑马鱼（Danio rerio）的发展和行动的基本机制是什么？（2）在皮质醇的什么水平上，母亲的这种贡献从必不可少转变为不健康，作用方式是什么？iii）皮质类固醇信号传导对早期发育至关重要吗？作用方式是什么？使用斑马鱼和虹鳟鱼（Oncorhynchus mykiss）的科学方法将涉及多层次的组织研究，包括整个动物，组织和体外细胞制备，基因敲除研究和胚胎转录组分析，以阐明发育过程中皮质醇作用的分子机制。拟议的研究是变革性的，将绘制一个新的课程，在压力研究的重点是如何后代表型是由父母的压力和异常皮质醇沉积在鸡蛋。这一基础研究在环境和水产养殖领域具有潜在的应用价值，其中压力是影响表型的主要因素。发现新的皮质类固醇相关的目标参与发展规划也可能有助于我们了解胎儿应激相关的疾病和出生缺陷的哺乳动物。该计划是跨学科的，将培养至少九名研究生，三名PDF和几名本科生，涉及生理学，分子生物学和发育生物学的前沿研究。

My research program seeks to discover novel cellular signals and transduction pathways modulated by the stress steroid cortisol, and to advance our fundamental knowledge of how these responses are integrated at the whole animal level to drive function. My short-term objective for this 5-year program, is to address the role played by maternal cortisol in programming the development of offspring stress axis function. The overriding hypothesis is that maternal stress and the associated increase in cortisol deposition to the embryo will decrease cortisol clearance mechanisms prior to hatch and will lead to dysfunctions to offspring corticosteroid stress axis performance. Three specific concepts are being addressed: i) Is maternally transferred cortisol absolutely essential for zebrafish (Danio rerio) development and what are the underlying mechanisms of action? ii) At what level of cortisol does this maternal contribution switch from being essential to unhealthy and what is the mode of action? iii) Is corticosteroid signaling essential for early development and what is the mode of action? The scientific approach using zebrafish and rainbow trout (Oncorhynchus mykiss) will involve studies at multiple levels of organization, including whole animal, tissue and in vitro cell preparations, gene knockdown studies and embryo transcriptome profiling, to elucidate the molecular mechanisms involved in cortisol action during development. The proposed studies are transformative and will chart a new course in stress research with the focus on how offspring phenotype is dictated by parental stress and abnormal cortisol deposition in eggs. This fundamental research has potential applications in environmental and aquaculture sectors where stress is a major factor affecting phenotype. The discovery of novel corticosteroid-related targets involved in developmental programming may also assist in our understanding of fetal stress-related disorders and birth defects in mammals. This program is interdisciplinary and will train at least nine graduate students, three PDFs and several undergraduate students in cutting edge research involving physiology, molecular biology and developmental biology.****