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

斑马鱼胚胎和幼虫的神经内分泌免疫（NEI）系统编程：对应激恢复能力、抗病能力和寿命的影响

• 批准号: RGPIN-2019-03903
• 负责人: Karrow, Niel
• 金额: $ 2.4万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714090
• 关键词: Neuroendocrine; immune; NEI; system; programming

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.

牲畜和水产养殖物种通常会受到各种压力源，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压力的反应方面起着核心作用，并有助于在压力事件发生后恢复生理稳态。 NEI系统对产前和围产期应激源敏感，当它们在某些开发窗口中经历时，NEI系统编程可能会永久影响；尽管父亲的压力可能同样重要，但研究人员历史上一直关注孕产妇和新生儿压力。有人提出，早期发育过程中的NEI可塑性是一种适应性机制，可帮助新生动物为产后环境做准备。但是，当发展性编程与最终居住的后代的环境不匹配时，它可能会对压力弹性，抗病性和寿命产生负面影响，所有这些都是重要的健康，经济和福利对加拿大牲畜和水产养殖生产者的关注。人类的研究表明，通过养分限制，创伤经历和微生物感染等压力源可以表现出应激源，从而跨几代人表现出压力诱导的NEI系统编程，并且性别差异很常见。压力引起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尚不清楚。发生应力引起的编程的作用机制（MOA）才刚刚开始被理解，并且似乎涉及基因调节的永久变化。 家庭动物研究的一个主要局限性是它们非常昂贵且耗时，尤其是在研究世代，父母和性别影响和MOA时。我们认为，斑马鱼（ZF）是一种新兴的脊椎动物模型，有可能极大地促进我们对压力如何影响牲畜和水产养殖物种中的NEI编程的理解。在此提案中，我们计划使用先天免疫应激源（微生物相关的分子模式； MAMP）开发幼虫和成人ZF免疫应激模型，以研究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。由于鱼缺乏重要的哺乳动物模式识别受体（PRR）直系同源物，类似于收费的受体4（TLR4），因此鉴定其他促进TLR4配体的MAMP识别的PRR将很重要。这些可能是基于营养的或疫苗指导的免疫刺激的替代靶标，并且它们可能是各种物种的多态性的，这对于增强疾病抗性的遗传选择非常重要。这项研究将有助于我们更好地理解压力引起的NEI系统编程在发育中的动物中的长期影响，并使我们能够调查植物化学物质可能调节的监管过程，以促进后代健康而不依赖抗菌药物。