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

牲畜和水产养殖物种经常受到各种压力，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，并有助于在应激事件后恢复生理稳态。NEI系统对产前和围产期压力敏感，当它们在发育的某些窗口期间经历时，NEI系统编程可能会受到永久性影响;研究人员历史上一直专注于母亲和新生儿压力，尽管父亲压力可能同样重要。有人提出，NEI可塑性在早期发展是一种适应机制，帮助新生动物准备其出生后的环境;然而，当发育规划是不匹配的环境，后代最终居住，它可能会产生负面影响的压力恢复能力，抗病能力和寿命，所有这些都是重要的健康，经济和福利问题加拿大畜牧业和水产养殖生产者。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，发育中的NEI系统的应激诱导编程可以在几代人之间表现出来，性别差异很常见;应激诱导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。应激诱导编程发生的作用机制（MOA）才刚刚开始被理解，似乎涉及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，它们非常昂贵和耗时，特别是在研究世代、父母和性别影响以及MOA时。我们相信，斑马鱼（Zf），这是一种新兴的脊椎动物模型，有可能大大提高我们对压力如何影响NEI规划在畜牧业和水产养殖物种的理解。在这项提案中，我们计划开发幼虫和成人Zf免疫应激模型使用先天免疫应激（微生物相关的分子模式; MAMPs）研究NEI系统的应激诱导的编程，研究植物化学物质提供的保护，并探索MOA。由于鱼类缺乏一个重要的哺乳动物模式识别受体（PRR）的直系同源物，Toll样受体4（TLR 4），这将是重要的是要确定其他PRR，促进识别MAMPs TLR 4配体;这些可能作为替代目标的营养为基础的或疫苗导向的免疫刺激，它们可能是多态性的物种，这将是重要的遗传选择，以提高抗病性。这项研究将帮助我们更好地了解应激诱导的NEI系统编程对发育中动物的长期影响，并使我们能够研究可能由植物化学物质调节的调节过程，以促进后代的健康，而不依赖于抗菌剂。

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.*****