The life-long effects of maternal milk: programming offspring development

母乳的终生影响：规划后代发育

• 批准号: RGPIN-2022-03805
• 负责人: Wijenayake, Sanoji
• 金额: $ 2.04万
• 依托单位: University of Winnipeg
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745943
• 关键词: life; long; effects; maternal; milk

In Canada, 22-24% of women are diagnosed with obesity at the time of conception. Maternal obesity is not only associated with negative outcomes for the mother, but it can impact fetal and postnatal development and the overall health of offspring in later life. Maternal milk consumption is proposed as a solution to combat the risks of obesity in offspring. However, very little is known about the underlying biological mechanisms that infer this protective effect and how maternal nutrition may influence the composition and function of the non-nutritive, bioactive components of milk. Mammalian milk is a complex biological fluid that contains a plethora of bioactive components. My focus is on a group of small, fat-coated, bioactive vesicles known as milk-derived exosomes (MDEs). MDEs are a unique subpopulation of extracellular vesicles that survive digestion, travel long-distances (gut to the brain), and carry genetic information from mothers to their offspring. One of the main types of genetic information packaged within MDEs, is milk microRNAs (miRNAs), small RNA that blocks protein production in recipient cells. This establishes a novel, post-birth molecular route of mother-offspring communication, that is heavily understudied. My long-term objective is to characterize the role of MDEs and milk miRNAs as biological regulators in early postnatal development. Over the next five years, I will address four short-term objectives: 1) using cell culture and a rodent model map the cellular and molecular mechanisms of MDEs and milk miRNA transfer across the gut and into the brain, 2) quantify changes in MDE and milk miRNA composition across milk types and lactation age, 3) explore how maternal nutrition stress affect lactation biology of the mother, and 4) how does changes in lactation biology influence developmental trajectories in offspring. Completing studies under objective 1 will enable me to understand the cellular mechanisms that control MDE and milk miRNA transport in tissues (especially in the brain, where very little information is known to date). Objective 2 will build on objective 1 to characterize temporal changes in the composition of MDEs and miRNAs in milk type (colostrum and mature milk). Addressing objective 3 and 4 will allow me to expand my research into the developmental origins of health and disease field, where milk-induced phenotypic and physiological outcomes in offspring due to maternal nutrition stress will be investigated. My aim is to improve our understanding of the molecular basis of lactation biology and identify novel methods of postnatal communication between mother and child. I anticipate that my research will identify genes and developmental pathways that are regulated by MDEs and milk miRNAs. Mechanistic insights obtained from this research can be used to improve nutritional benefits of donor and formula feeding, where MDE and milk miRNA-based signalling is absent.

在加拿大，22%-24%的女性在怀孕时被诊断为肥胖。母亲肥胖不仅与母亲的负面后果有关，而且会影响胎儿和出生后的发育以及后代在以后的生活中的整体健康。母乳摄取被认为是对抗后代肥胖风险的一种解决方案。然而，人们对推断这种保护作用的潜在生物学机制以及母亲营养如何影响牛奶中非营养、生物活性成分的组成和功能知之甚少。哺乳动物奶是一种复杂的生物流体，含有过多的生物活性成分。我的重点是一组小的、包裹着脂肪的、具有生物活性的囊泡，称为乳源性外切体(MDES)。MDE是一种独特的胞外囊泡亚群，它们能在消化过程中存活下来，长距离(肠道到大脑)运输，并将遗传信息从母亲那里传递给后代。MDES中打包的遗传信息的主要类型之一是牛奶微RNA(MiRNAs)，这是一种阻止受体细胞中蛋白质生产的小RNA。这建立了一种新颖的、出生后母子沟通的分子途径，但研究严重不足。我的长期目标是确定MDES和牛奶miRNAs在出生后早期发育中作为生物调节因子的作用。在接下来的五年里，我将致力于四个短期目标：1)利用细胞培养和啮齿动物模型绘制MDE和乳中miRNA跨肠道和进入大脑的细胞和分子机制图；2)量化MDE和乳中miRNA组成在不同乳类和哺乳期之间的变化；3)探讨母亲营养应激如何影响母亲的哺乳期生物学；4)哺乳期生物学的变化如何影响后代的发育轨迹。完成目标1下的研究将使我能够了解控制MDE和牛奶miRNA在组织中运输的细胞机制(特别是在大脑中，迄今知之甚少)。目标2将以目标1为基础，描述牛奶类型(初乳和成熟奶)中MDES和miRNAs组成的时间变化。解决目标3和4将使我能够将我的研究扩展到健康和疾病领域的发育起源，其中将调查母体营养压力引起的牛奶诱导后代的表型和生理结果。我的目的是提高我们对哺乳生物学的分子基础的理解，并确定母子之间出生后沟通的新方法。我预计我的研究将确定受MDES和牛奶miRNAs调控的基因和发育途径。从这项研究中获得的机械性见解可用于改善缺乏MDE和牛奶miRNA信号的捐赠者和配方奶的营养效益。