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

在加拿大，22-24%的女性在怀孕时被诊断患有肥胖症。母亲肥胖不仅与母亲的负面结果有关，而且会影响胎儿和产后发育以及后代在以后生活中的整体健康。母乳消费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体营养如何影响乳汁中非营养性生物活性成分的组成和功能知之甚少。哺乳动物乳是一种复杂的生物液体，含有大量生物活性成分。我的重点是一组小的，脂肪涂层，生物活性囊泡称为乳源性外泌体（MDEs）。MDE是一种独特的细胞外囊泡亚群，能够在消化中存活，长距离旅行（肠道到大脑），并将遗传信息从母亲传递给后代。MDE中包装的主要遗传信息类型之一是牛奶microRNAs（miRNAs），这是一种阻止受体细胞中蛋白质产生的小RNA。这建立了一个新的，出生后的母子沟通的分子途径，这是严重不足的研究。我的长期目标是描述MDE和牛奶miRNAs在出生后早期发育中作为生物调节剂的作用。在未来五年，我将提出四个短期目标：1）使用细胞培养物和啮齿动物模型绘制MDE和乳汁miRNA跨肠道转移并进入大脑的细胞和分子机制，2）量化不同乳汁类型和泌乳年龄的MDE和乳汁miRNA组成的变化，3）探索母体营养应激如何影响母亲的泌乳生物学，以及4）哺乳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在组织中转运的细胞机制（特别是在大脑中，迄今为止信息很少）。目标2将建立在目标1的基础上，以表征乳汁类型（初乳和成熟乳）中MDE和miRNA组成的时间变化。解决目标3和4将使我能够扩大我的研究到健康和疾病领域的发展起源，在那里牛奶诱导的表型和生理结果的后代由于母亲营养压力将进行调查。我的目的是提高我们对哺乳生物学分子基础的理解，并确定母亲和孩子之间产后沟通的新方法。我预计我的研究将确定由MDEs和牛奶miRNA调控的基因和发育途径。从这项研究中获得的机制见解可用于改善供体和配方喂养的营养益处，其中MDE和基于牛奶miRNA的信号传导不存在。

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.