Developmental Programming by Mismatch of Pre-and Postnatal Nurtition

描述（由申请人提供）：发育规划（DP）定义为-胎儿或新生儿生命关键窗口期对改变正常发育的挑战的反应，从而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，妊娠期母体营养减少（MNR）导致胎儿营养减少（FNR），而限制哺乳(L)可能使后代（OFF）易患肥胖和其他慢性疾病。如果FNR后的产后营养不良，P中MNR母亲的OFF会发展出节俭表型，以更好地生存。-“预测性适应性反应”。在啮齿类动物中，与过量（甚至正常）新生儿营养不匹配的FNR也使OFF易患慢性疾病。在一项针对MNR的R24研究中（MNR R24），我们建立了狒狒OFF队列，1)对照（CTR）狒狒在P和L中自由进食- CTR/CTR （P饮食第一，L饮食第二）和2)MNR狒狒在70%的全球体重调整CTR （MNR/MNR）中进食。这款R24在2009年6月才完成。在那之后的一年里，共有11份拨款申请提交，其中6份获得成功。第二项R24研究于2010年2月开始，研究对象是喂养高能量饮食（HED）的母亲，这些母亲在P和L中产生饮食诱导的母亲肥胖（MO/MO, MO R24）。具体目的：建立非人类灵长类动物（NHP）在胎儿和新生儿生活中暴露于营养不匹配（MM）的队列- MNR/CTR和MNR/MO作为多研究者资源来研究机制（MM R24）。我们致力于发展队列来比较人类DP的潜在机制。我们现在有三个队列——CTR/CTR， MNR/MNR, MO/MO。在其他6个潜在队列中，CTR/MNR、CTR/MO和MO/MNR三个组的兴趣不大。我们建议发展MNR/CTR和MNR/MO的队列，因为正如我们所包含的几封信所示，错配是DP的核心——两位权威甚至将他们的书命名为错配。治疗方法：控制食物摄入，保持正常的社交和身体活动。最近获得资助的MO R24如果获得资助，将为该MM R24提供同步CTR妊娠-节省33%的成本。在P期，相似表型的狒狒将被喂食70%的CTR （MNR）。出生后，MNR母亲被免费喂养，要么是食物，要么是HED。断奶后吃些食物。13封新信（全部来自圣安东尼奥以外，4封来自美国以外）被添加到之前的24封信中，显示出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、研究人员和创新：pi和SFBR为这项工作提供了独特的设施、动物和专业知识组合。自1976年以来，pi一直持有NHLBI， NICHD， NEI， NINCDS, NIA NIMH， NIDDK的合作资金。早发型NHP有广泛的MM研究，但未见早发型NHP的研究，其中关键的产前和新生儿环境因素- P02，葡萄糖，激素有很大差异。拟议的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）相关的DP提供了新的机会。资源共享：我们将对该资源进行归档、宣传和共享。

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.