Biochemical Development of the Fetus/Neonate and Maternal Diet

自成立以来，我的研究计划已经调查了胎儿和新生儿的生化发育，其总体目标是确定围产期生长和器官发育的营养和非营养决定因素。四个新的实验方法已被使用。这些包括（1）羊水（AF）的营养成分的表征，所述羊水被生长中的胎儿连续地吞咽并且可以提供胎儿的早期生物化学发育的重要的第一窗口;（2）探索乳汁中的新的生物活性成分，包括但不限于炎性标志物和细胞因子，以及它们对出生后生长和发育的影响;以及（3）调查胃肠道线虫感染与营养缺乏相结合时损害围产期生长和器官发育的机制。 在我上一次获得NSERC资助的任期内，每一种方法都产生了新的见解。首先，有证据表明，AF中的主要蛋白质白蛋白可以被不可逆地氧化，这表明膳食抗氧化剂在妊娠早期具有重要但未被充分认识的作用。其次，母体蛋白质缺乏和感染通过增加促炎细胞因子和降低血浆和乳汁中生长因子的浓度而损害免疫发育。第三，蛋白质缺乏和感染损害胎儿和新生儿的生长和器官发育不同，这些差异与血浆，羊水和乳汁中皮质醇，生长因子，促炎细胞因子浓度的重要房室变化有关。 当前发现补助金的总体目标是继续探索围产期生长和发育的生化决定因素，具体目标如下：目的1：第一个目标将探索羊水营养物质和新出现的生物活性成分（miRNAs，EPO，细胞因子和生长因子）如何促进早期胎儿生长的调节。第二种方法是探索氧化应激本身是否会损害胎儿的生长，或者在AF中膳食抗氧化剂的存在是否会带来一些益处？目的2：乳腺炎是一种无症状的乳腺炎症，与乳汁微生物组的变化、乳汁细胞因子增加和生长受损相关。我们将探讨炎症诱导的乳汁成分（营养素/生长和免疫因子，微生物组）变化是否会损害新生儿的生长。目标3：第三个目的是探讨炎症和免疫，通常与胃肠道线虫感染和母体蛋白质缺乏症，如何影响围产期器官发育。第二个目的是确定这些变化是否是通过肠道微生物组的改变和/或发育中的胎儿和新生儿器官系统中基因转录物的差异表达而发生的。

Since its inception, my research program has investigated the biochemical development of the fetus and neonate with the overall goal of identifying nutritional and non-nutritional determinants of perinatal growth and organ development. Four novel experimental approaches have been used. These include (1) the characterization of the nutrient composition of amniotic fluid (AF) which is continuously swallowed by the growing fetus and may provide an important first window into the early biochemical development of the fetus; (2) an exploration of novel bioactive, components in milk, including but not limited to inflammatory markers and cytokines, and their impact on postnatal growth and development; and (3) an investigation into mechanisms by which gastrointestinal nematode infections when coupled with nutritional deficiencies impair perinatal growth and organ development. During the tenure of my last NSERC grant, each approach resulted in new insights. First, evidence emerged to show that albumin, the major protein in AF, can be irreversibly oxidized, suggesting an important but underappreciated role for dietary antioxidants early in pregnancy. Secondly maternal protein deficiency and infection impaired immune development by increasing pro-inflammatory cytokines and lowering concentrations of growth factors in plasma and in milk. Thirdly protein deficiency and infection impaired fetal and neonatal growth and organ development differently and these differences were associated with important compartmental changes in concentrations of cortisol, growth factors, proinflammatory cytokines in plasma, amniotic fluid and in milk. The overarching goal of the current discovery grant is to continue to explore the biochemical determinants of perinatal growth and development with following specific aims: AIM 1: The first aim will explore how amniotic fluid nutrients and newly emerging bioactive constituents (miRNAs, EPO, cytokines and growth factors) contribute to the regulation of early fetal growth. A secondary approach is to explore if oxidative stress itself impairs fetal growth or will the presence of dietary antioxidants in AF be of some benefit? AIM 2: Mastitis, an asymptomatic breast inflammation, is associated with changes in the milk microbiome, increased milk cytokines and impaired growth. We will explore if inflammation induced changes in milk composition (nutrients/growth & immune factors, microbiome) impair neonatal growth. AIM 3: The third aim explores how inflammation and immunity, commonly associated with gastrointestinal nematode infections and maternal protein deficiency, impact perinatal organ development. A secondary objective is to determine if these changes occur through alterations in the intestinal microbiome and/or differential expression on gene transcripts in developing fetal and neonatal organ systems?