Cortisol stress axis development and function in fish

我的研究计划旨在发现受应激类固醇皮质醇调制的新的细胞信号和转导途径，并推进我们关于这些反应如何在整个动物水平上整合以驱动功能的基础知识。我对这个为期5年的计划的短期目标是解决母亲皮质醇在规划子代应激轴功能发展中所起的作用。最重要的假设是，母体应激和相关的皮质醇沉积到胚胎的增加将降低孵化前皮质醇清除机制，并将导致子代皮质类固醇应激轴功能障碍。正在讨论三个具体概念：i)母体转移的皮质醇对斑马鱼(Danio Rerio)的发育是绝对必要的吗？潜在的作用机制是什么？Ii)在什么水平的皮质醇中，这种母体的贡献从必需转变为不健康，其作用模式是什么？3)皮质类固醇信号对早期发育是必要的吗？作用方式是什么？使用斑马鱼和虹鲑鱼的科学方法将涉及多个组织水平的研究，包括整个动物、组织和体外细胞准备、基因敲除研究和胚胎转录组图谱，以阐明发育过程中皮质醇作用的分子机制。这项拟议的研究具有变革性，将为应激研究开辟一条新的道路，重点关注亲本应激和卵子中皮质醇异常沉积如何决定后代的表型。这项基础性研究在环境和水产养殖领域具有潜在的应用前景，在这些领域，压力是影响表型的主要因素。涉及发育规划的新的皮质类固醇相关靶点的发现也可能有助于我们理解哺乳动物的胎儿应激相关疾病和出生缺陷。该项目是跨学科的，将培训至少9名研究生、3名PDF和几名本科生从事涉及生理学、分子生物学和发育生物学的尖端研究。

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.