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通常会受到不同类型的压力源，例如微生物感染。神经内分泌 - 免疫（NEI）系统在安装和调节宿主对压力源的反应方面起着核心作用，并有助于在压力事件通过后恢复生理平衡。发育中的NEI系统对产前和产后应力（PPS）非常敏感，当在某些开发窗口中经历PPS时，NEI系统的基因编程可能会永久影响。有人提出，这种Nei延展性是一种适应性机制，可帮助新生动物为其新的环境做准备。但是，如果NEI编程与产后环境不匹配，则可能对后代应力弹性，抗病性和寿命产生负面影响。所有这些都是加拿大牲畜和水产养殖部门（班级）的重要健康，福利和经济关注。人类的研究表明，压力引起的发育编程的影响可以在几代人之间表现出来，并且性别特定的反应很常见。但是目前尚不清楚这对班级的影响。研究人员历来关注孕产妇和新生儿压力。但是，父亲的压力似乎同样重要。发生NEI系统编程的作用机理（MOA）才开始被理解，并且似乎涉及影响基因调节的表观遗传学变化。 ***在该研究领域进行大型动物研究的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）是人类生理和疾病的建立模型，有可能在该领域大大提高阶级研究。在此提案中，我们计划使用细菌脂多糖（LPS）内毒素免疫刺激（BEIS）开发ZF PPS模型； LPS构成了革兰氏阴性细菌（例如大肠杆菌）的细胞膜，并且通常用于研究细菌感染。然后，这些PPS模型将用于评估beis应力之后的幼虫和新生儿NEI编程，包括MOA。由于FISH缺乏哺乳动物所具有的主要LPS受体，即Toll样受体4，因此必须识别能够识别LPS识别的受体。这些可以用作营养和疫苗诱导的先天免疫刺激的替代靶标，并且可能是各种物种多态性的，这对于遗传选择很重要。这项研究将有助于我们更好地了解PPS对发展动物的长期影响，并使我们能够调查调节过程，以增强班级中饲养的动物的整体压力弹性，抗病性和寿命，而无需依靠抗生素来预防新生儿疾病。