Neuroendocrine-immune (NEI) system programming of zebrafish embryos and larva: Implications for stress resilience, disease resistance, and longevity

家畜和水产养殖物种经常受到各种压力因素的影响，例如微生物感染。神经内分泌-免疫(NEI)系统在启动和调节宿主对应激的反应中起着核心作用，并帮助在应激事件后恢复生理平衡。NEI系统对产前和围产期应激源很敏感，当它们在某些发育窗口经历时，NEI系统的规划可能会受到永久性影响；研究人员历来专注于母亲和新生儿的压力，尽管父亲的压力可能同样重要。有人提出，早期发育中的NEI可塑性是一种帮助新生动物为出生后环境做准备的适应机制；然而，当发育规划与后代最终居住的环境不匹配时，可能会对应激恢复、抗病和寿命产生负面影响，所有这些都是加拿大畜牧业和水产养殖生产者关心的重要健康、经济和福利问题。人类研究表明，通过营养限制、创伤经历和微生物感染等应激源，应激诱导的正在发育的NEI系统的编程可以在世代之间表现出来，性别差异很常见；应激诱导的编程对牲畜和水产养殖物种的NEI系统的影响在很大程度上是未知的。发生应激诱导编程的作用机制(MOA)刚刚开始被理解，似乎涉及到基因调控的永久性变化。 家养动物研究的一个主要局限性是，它们的执行极其昂贵和耗时，特别是在调查世代、父母和性别影响以及MOA时。我们相信斑马鱼(ZF)，这是一个新兴的脊椎动物模型，有潜力极大地促进我们对压力如何影响牲畜和水产养殖物种的NEI编程的理解。在这项提议中，我们计划利用先天性免疫应激源(微生物相关分子模式；MAMPs)建立幼虫和成虫ZF免疫应激模型，以研究应激诱导的NEI系统编程，调查植物化学物质提供的保护，并探索MOA。由于鱼类缺乏一种重要的哺乳动物模式识别受体(PRR)同源物Toll样受体4(TLR4)，因此重要的是确定其他有助于识别属于TLR4配体的MAMP的PRR；这些MAMP可能作为基于营养的或疫苗导向的免疫刺激的替代靶标，并且它们可能在不同物种之间具有多态，这对于提高疾病抵抗力的遗传选择将是重要的。这项研究将帮助我们更好地了解应激诱导的NEI系统编程对发育动物的长期影响，并使我们能够调查可能受植物化学物质调节的调控过程，以促进后代健康，而不依赖抗菌素。

Livestock and aquaculture species are routinely subjected to a variety of stressors such as microbial infections. The neuroendocrine-immune (NEI) system plays a central role in initiating and regulating the host response to stress and helps restore physiological homeostasis after a stress event. The NEI system is sensitive to prenatal and perinatal stressors, and when they are experienced during certain windows of development, NEI system programming can be permanently affected; researchers have historically focused on maternal and neonatal stress, although paternal stress may be equally important. It has been proposed that NEI plasticity during early development is an adaptive mechanism that helps newborn animals prepare for their postnatal environment; however, when developmental programming is mismatched to the environment that offspring ultimately reside in, it may negatively impact stress resilience, disease resistance and longevity, all of which are important health, economic and welfare concerns for Canadian livestock and aquaculture producers. Human studies have shown stress-induced programming of the developing NEI system, by stressors such as nutrient restriction, traumatic experiences and microbial infection, can manifest across generations, and sex differences are common; the impact of stress-induced programming on the NEI systems of livestock and aquaculture species is largely unknown. The mechanisms of action (MOA) by which stress-induced programming occurs are just beginning to be understood and appear to involve permanent changes in gene regulation. A major limitation of domestic animal studies is that they are extremely costly and time consuming to perform, especially when generational, parental and sex effects, and MOA are investigated. We believe the zebrafish (Zf), which is an emerging vertebrate model, has the potential to greatly advance our understanding of how stress impacts NEI programming in livestock and aquaculture species. In this proposal, we plan to develop larval and adult Zf immune stress models using innate immune stressors (microbial-associated molecular patterns; MAMPs) to study stress-induced programming of the NEI system, investigate protection provided by phytochemicals, and explore MOA. Since fish lack an important mammalian pattern-recognition receptor (PRR) orthologue, Toll-like receptor 4 (TLR4), it will be important to identify other PRR that facilitate recognition of MAMPs that are TLR4 ligands; these may serve as alternate targets for nutrition-based or vaccine-directed immune stimulation, and they may be polymorphic across species, which will be important for genetic selection to enhance disese resistance. This research will help us to better understand the long-term impact of stress-induced NEI system programming in developing animals and will allow us to investigate regulatory processes that may be modulated by phytochemicals to promote offspring health without relying on antimicrobials.