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

神经内分泌免疫系统的产前和产后规划：对应激恢复能力、抗病能力和长寿的影响

• 批准号: RGPIN-2018-04806
• 负责人: Karrow, Niel
• 金额: $ 2.11万
• 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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=655146
• 关键词: Pre; post; natal; programming; neuroendocrine

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.

牲畜和水产养殖物种经常受到不同类型的压力源，如微生物感染。神经内分泌免疫（NEI）系统在宿主对应激源的反应中起着中心作用，并在应激事件过去后帮助恢复生理平衡。发育中的NEI系统对产前和产后应激（PPS）非常敏感，当PPS在发育的某些窗口期经历时，NEI系统的遗传编程可能受到永久性的影响。有人提出，这种NEI延展性是一种适应性机制，可以帮助新生动物为新环境做好准备；然而，如果NEI编程与出生后的环境不匹配，它会对后代的应激恢复能力、抗病能力和寿命产生负面影响；所有这些都是加拿大畜牧业和水产养殖业的重要健康、福利和经济问题（类）。人类研究表明，压力诱发的发育程序的影响可以跨代表现出来，性别特异性反应很常见；但这对CLASs的影响目前尚不清楚。研究人员历来关注孕产妇和新生儿的压力；然而，来自父亲的压力似乎也同样重要。NEI系统编程发生的作用机制（MOAs）才刚刚开始被理解，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，特别是在调查代际、亲代和性别影响以及moa时。我们相信斑马鱼（Zf）是一种成熟的人类生理和疾病模型，有潜力极大地推进这一领域的CLASs研究。本课题拟采用细菌脂多糖（LPS）内毒素免疫刺激（BEIS）建立Zf - PPS模型；脂多糖构成了革兰氏阴性菌（如大肠杆菌）的细胞膜，通常用于模拟细菌感染的研究。然后，这些PPS模型将用于评估在BEIS压力下的幼虫和新生儿NEI规划，包括moa。由于鱼类缺乏哺乳动物所拥有的主要LPS受体toll样受体4，因此确定能够识别LPS的受体将是重要的；它们可以作为营养和疫苗诱导的先天免疫刺激的替代靶点，并且可能在物种间具有多态性，这对遗传选择很重要。这项研究将帮助我们更好地了解PPS对发育中的动物的长期影响，并使我们能够研究调节的过程，以提高在CLASs中饲养的动物的整体应激恢复能力、抗病能力和寿命，而不依赖于抗菌剂来预防新生儿疾病。