Developmental Programming by Mismatch of Pre-and Postnatal Nurtition

描述（由申请方提供）：发育规划（DP）定义为-在胎儿或新生儿生命的关键窗口期对挑战的反应，这些挑战改变了正常发育，对表型产生持续影响，通过基因-环境相互作用改变表型。在啮齿类动物中，妊娠期（P）母体营养减少（MNR）导致胎儿营养减少（FNR），这可能与哺乳期（L）限制有关，使后代（OFF）易患肥胖症和其他慢性疾病。如果产后营养不良发生在FNR之后，P中MNR母亲的OFF会发展出节俭表型以更好地生存。- 一种“预测性适应反应。“啮齿类动物的FNR，与过量（甚至正常）的新生儿营养不匹配，也容易导致慢性疾病。在解决MNR的R24（MNR R24）中，我们开发了狒狒OFF队列，包括1）对照（CTR）狒狒，以P和L-CTR/CTR（首先是P饲料，其次是L饲料）随意饲喂，和2）MNR狒狒，以70%总重量调整的CTR（MNR/MNR）饲喂。这款R24直到2009年6月才完成。自那以后的一年里，共提交了11份赠款申请，其中6份成功。2010年2月开始了第二个R24，以开发喂养高能量饮食（HED）的母亲的OFF队列，这些母亲在P和L中产生饮食诱导的母亲肥胖（MO）（MO/MO，MO R24）。具体目标：开发在胎儿和新生儿生命中暴露于营养不匹配（MM）的非人灵长类动物（NHP）OFF队列- MNR/CTR和MNR/MO，作为研究机制的多研究者资源（MM R24）。我们致力于开发队列来比较人类DP的潜在机制。我们现在有三个队列- CTR/CTR，MNR/MNR，MO/MO。在其他六个潜在的队列中，CTR/MNR、CTR/MO和MO/MNR的兴趣不大。我们建议开发MNR/CTR和MNR/MO的队列，因为正如我们包括的几封信所显示的那样，不匹配是DP的核心-两个当局甚至将他们的书命名为Mismatch。方法：我们控制食物摄入，保持正常的社交和身体活动。最近资助的MO R24提供了该MM R24的同期CTR妊娠，如果资助的话-节省了33%的成本。在P期间，相似表型的狒狒将喂食70%的CTR（MNR）。出生后，MNR母亲被随意喂食食物或HED。断奶后全部关食。13封新信件（均来自圣安东尼奥以外，4封来自美国以外）添加到24封先前信件中，显示对研究这些队列的广泛兴趣。我们还单独提供了13封来自主要DP流行病学家支持NHP工作的信件。环境、研究者和创新：PI和SFBR为这项工作提供了独特的设施、动物和专业知识。自1976年以来，PI已获得NHLBI，NICHD，NEI，NINCDS，NIA NIMH，NIDDK的合作资金。存在对晚期物种的广泛MM研究，但未对早熟NHP进行研究，其中关键的纳塔尔和新生儿环境因素- P02、葡萄糖、激素非常不同。拟定的MM R24加上三个正在进行的队列为多个NIH研究所（NHLBI、NIDDK、NICHD、NIAID、NEI、NCI、NIA、NINDS、NIMH和NIEHS）提供了DP相关的新机会。资源共享：我们将存档，广告和共享此资源。

DESCRIPTION (provided by applicant): Developmental Programming (DP) defined as - responses to challenges in a critical window of fetal or neonatal life that alter normal development with resulting persistent effects on phenotype, modifies phenotype by gene-environment interaction. In rodents, maternal nutrient reduction (MNR) in pregnancy (P) leads to fetal nutrient reduction (FNR), which may be compounded by restriction in lactation (L) predisposing offspring (OFF) to obesity and other chronic conditions. OFF of MNR mothers in P develop a thrifty phenotype to better survive if poor post-natal nutrition follows FNR. - A "predictive adaptive response." FNR in rodents, mismatched by excess (or even normal) neonatal nutrition also predisposes OFF to chronic disease. In an R24 addressing MNR (MNR R24) we developed baboon OFF cohorts of 1) control (CTR) baboons fed ad lib in P and L - CTR/CTR (P diet first, L second) and 2) MNR baboons fed 70% global weight adjusted CTR (MNR/MNR). This R24 only finished in June 2009. In the year since, 11 grant applications have been submitted - six successfully. A second R24 to develop cohorts of OFF of mothers fed a high energy diet (HED) producing dietary induced maternal obesity (MO) in P and L (MO/MO, MO R24) began February 2010. Specific Aim: To develop cohorts of nonhuman primate (NHP) OFF exposed to nutrient mismatch (MM) in fetal and neonatal life - MNR/CTR and MNR/MO as a multi-investigator resource to study mechanisms (MM R24). We are committed to developing cohorts to compare mechanisms underlying human DP. We now have three cohorts- CTR/CTR, MNR/MNR, MO/MO. Of the six other potential cohorts three, CTR/MNR, CTR/MO and MO/MNR hold little interest. We propose to develop cohorts of MNR/CTR and MNR/MO because, as the several letters we include show, mismatch is central to DP- two authorities even entitle their book Mismatch. Approach: We control food intake, maintaining normal social and physical activity. The recently funded MO R24 provides contemporaneous CTR pregnancies for this MM R24 if funded - a 33% saving in cost. During P baboons of similar phenotype will be fed 70% of CTR (MNR). After birth, MNR mothers are fed ad lib either chow or HED. After weaning all OFF eat chow. Thirteen new letters (all from outside San Antonio, 4 outside USA) are added to the 24 prior letters showing wide-spread interest in studying these cohorts. We also separately provide 13 letters from leading DP epidemiologists supporting NHP work. Environment, Investigators and Innovation: PIs and SFBR provide a unique combination of facilities, animals and expertise for this work. PIs have held collaborative NHLBI, NICHD, NEI, NINCDS, NIA NIMH, NIDDK funding since 1976. Extensive MM studies exist on altricial species but not precocial NHP in which key pre- natal and neonatal environmental factors - P02, glucose, hormones are very different. The proposed MM R24 plus three on-going cohorts provide novel opportunities in DP relevant to multiple NIH institutes (NHLBI, NIDDK, NICHD, NIAID, NEI, NCI, NIA, NINDS, NIMH and NIEHS). Resource sharing: We will archive, advertise and share this resource.