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遭受不同类型的压力源，例如微生物感染。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方面发挥着核心作用，并有助于在应激事件过去后恢复生理平衡。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，这种 NEI 可塑性是一种适应机制，可以帮助新生动物为新环境做好准备。然而，如果 NEI 编程与产后环境不匹配，可能会对后代的抗应激能力、抗病能力和寿命产生负面影响；所有这些都是加拿大畜牧业和水产养殖业（CLAS）的重要健康、福利和经济问题。人类研究表明，压力诱发的发育规划的影响可以在几代人之间显现出来，并且性别特异性反应很常见；但目前尚不清楚这对 CLAS 的影响。研究人员历来关注孕产妇和新生儿的压力。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) 刚刚开始被理解，并且似乎涉及影响基因调控的表观遗传学变化。 ***该研究领域大型动物研究的一个主要限制是其成本极高且耗时，特别是在研究世代、亲代和性别影响以及 MOA 时。我们相信斑马鱼（Zf）是一种完善的人类生理学和疾病模型，有潜力极大地推进该领域的 CLAS 研究。在本提案中，我们计划利用细菌脂多糖（LPS）内毒素免疫刺激（BEIS）开发Zf PPS模型； LPS 构成了大肠杆菌等革兰氏阴性细菌的细胞膜，通常用于模拟细菌感染的研究。这些 PPS 模型将用于评估 BEIS 应激后的幼虫和新生儿 NEI 编程，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，因此识别能够识别 LPS 的受体非常重要；这些可以作为营养和疫苗诱导的先天免疫刺激的替代目标，并且可能在物种间具有多态性，这对于遗传选择很重要。这项研究将帮助我们更好地了解 PPS 对发育中动物的长期影响，并使我们能够研究可调节的监管过程，以增强 CLAS 中饲养的动物的整体应激恢复能力、抗病能力和寿命，而无需依赖抗菌药物来预防新生儿疾病。