Pre- and post-natal programming of the neuroendocrine-immune system: Implications for stress resilience, disease resistance, and longevity

家畜和水产养殖物种经常受到不同类型的应激因素的影响，如微生物感染。神经内分泌-免疫(NEI)系统在建立和调节宿主对应激源的反应中起着核心作用，并帮助在应激事件过去后恢复生理平衡。发育中的NEI系统对出生前和出生后应激(PPS)非常敏感，当在某些发育窗口经历PPS时，NEI系统的遗传编程可能会受到永久性影响。有人提出，NEI的延展性是一种适应性机制，可以帮助新生动物为它们的新环境做准备；然而，如果NEI编程与出生后环境不匹配，它可能会对后代的应激能力、抗病能力和寿命产生负面影响；所有这些都是加拿大畜牧和水产养殖部门(类别)重要的健康、福利和经济问题。人类研究表明，压力诱导的发育规划的影响可以在几代人之间表现出来，性别特有的反应很常见；但这对班级的影响目前尚不清楚。研究人员历来关注母亲和新生儿的压力；然而，父亲的压力似乎同样重要。NEI系统编程发生的作用机制(MOA)才刚刚开始被理解，而且似乎涉及影响基因调控的表观遗传学变化。*在这一研究领域进行大型动物研究的一个主要限制是，进行这些研究非常昂贵和耗时，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)，这是一个公认的人类生理和疾病的模型，有潜力极大地推动这一领域的类别研究。在这项提案中，我们计划利用细菌脂多糖(LPS)内毒素免疫刺激(BEIS)建立ZF PPS模型；LPS组成革兰氏阴性细菌的细胞膜，如大肠杆菌，通常用于模拟细菌感染的研究。这些PPS模型随后将用于评估幼虫和新生儿的NEI编程，包括在BEIS应激后的MOA。由于鱼类缺乏哺乳动物拥有的主要内毒素受体Toll样受体4，因此识别能够识别内毒素的受体将是重要的；这些受体可以作为营养和疫苗诱导的先天免疫刺激的替代靶标，并且可能在不同物种之间具有多态，这对遗传选择很重要。这项研究将帮助我们更好地了解PPS对发育动物的长期影响，并将使我们能够研究PPS的调控过程可能被调节以增强班级饲养的动物的整体应激韧性、抗病能力和寿命，而不需要依赖抗菌剂来预防新生儿疾病。

Livestock and aquaculture species are often subjected to different types of stressors, like microbial infections. The neuroendocrine-immune (NEI) system plays a central role in mounting and regulating the host response to stressors, and helps restore physiological balance after a stress event has passed. The developing NEI system is very sensitive to prenatal and postnatal stress (PPS), and when PPS is experienced during certain windows of development, genetic programming of the NEI system can be permanently affected. It has been proposed that this NEI malleability is an adaptive mechanism that helps newborn animals prepare for their novel environment; however, if NEI programming is mismatched to the postnatal environment, it can negatively impact offspring stress resilience, disease resistance, and longevity; all of which are important health, welfare and economic concerns for the Canadian livestock and aquaculture sectors (CLASs). Human studies, have shown the effects of stress-induced developmental programming can manifest across generations, and sex-specific responses are common; but the impact of this on the CLASs is currently unknown. Researchers have historically focused on maternal and neonatal stress; however, paternal stress appears to be equally important. The mechanisms of action (MOAs) by which NEI system programming occurs are just beginning to be understood, and appear to involve epigenetics changes affecting gene regulation. ***A major limitation of large animal studies in this research area is that they are extremely costly and time consuming to conduct, especially when generational, parental and sex effects, and MOAs are investigated. We believe the zebrafish (Zf), which is a well-established model of human physiology and disease, has the potential to greatly advance CLASs research in this area. In this proposal, we plan to develop Zf PPS models using bacterial lipopolysaccharide (LPS) endotoxin immune stimulation (BEIS); LPS makes up the cell membrane of Gram-negative bacteria such as Escherichia coli, and is commonly used in research to simulate a bacterial infection. These PPS models will then be used to assess larval and neonatal NEI programming, including MOAs, following BEIS stress. Since fish lack the main LPS receptor possessed by mammals, Toll-like receptor 4, it will be important to identify receptors that enable LPS recognition; these can serve as alternative targets for nutrition- and vaccine-induced innate immune stimulation, and may be polymorphic across species, which is important for genetic selection. This research will help us to better understand the long-term impact of PPS on developing animals, and will allow us to investigate regulatory processes may be modulated to enhance overall stress resilience, disease resistance, and longevity of animals reared in the CLASs without relying on antimicrobials to prevent neonatal disease.