Project 2: Developmental Programming & Aging Interactions in Primate CV Function

项目2：灵长类动物CV功能的发育编程和衰老相互作用 摘要 研究狒狒的衰老可以产生有用的信息，以提高我们对衰老过程的理解， 人类全身心血管（CV）指标，尤其是心脏功能的心脏MRI评估， 结构，将与我们的胎儿和生命过程档案和CV中的心脏组织分析一起进行沿着评价 在正常生活情况下对相同动物进行测量，以评价 狒狒的衰老。这项研究计划包括研究人们在生命早期的压力， 从长远来看，子宫会改变心脏的正常老化。这项研究将由 表征来自MRI成像研究的参数（所谓的成像生物标志物）并比较 它们与每只动物的表型，包括功能，结构和分子生物学测量， 可以用来预测衰老相关的变化。在96只狒狒（6-18岁; 人~20-70岁）将表征左和右心室功能、主动脉扩张性、心肌 细胞外容积，心脏脂肪变性，肌丝蛋白表达，心率变异性，压力感受器 反应和循环的microRNA。在所有组中，我们研究了相同数量的男性和女性。这些 将为所有三个目标进行测量。在目标1中，将研究正常生命过程狒狒（N=48） 建立标准值，并作为年龄匹配的控制组研究在随后的目标。在所有 在动物中，我们将把获得的数据与微阵列数据、组织活检和系统代谢数据相关联， MRI测量心肌老化变化。在目标2中，母亲的后代（F1）受到中度（30%） 将研究妊娠期和哺乳期热量限制（N=16）以及肥胖母亲（OM）的后代 在怀孕期间喂食高脂肪、高果糖饮食（N=16）。研究有这些情况的狒狒会有所帮助 区分对心肌结构和功能的直接影响与对 由于正常的衰老。在目标3中，我们将确定老化轨迹是否会在 亚组（N=16），使用皮质醇替代干预（CRI）激发。我们将使用相同的方法对所有 所有条件下的动物，以评价归因于年龄相关的心血管功能变化 流程.重要的是，在本项目（项目2）中评价CV参数的相同动物 也正在研究其他项目的神经内分泌，大脑和行为功能（项目1）， 和代谢老化（项目3）。自01年提交以来，我们可以报告5篇发表在 狒狒模型中的心脏代谢效应：3篇发表在J Physiology，1篇发表在J Devel Origins Health Dis 一个在Int J Obes（Lond）。对审查的回应：我们对主要的弱点作出回应，即 饮食，缺乏胎儿的方法，并概述了我们的档案的价值，现在我们不执行安乐死在 IRG的要求。我们展示了我们的效应量是如何高的，我们的受试者数量是在最高端的。 任何非人类灵长类动物在过去提供良好的意义，并确保强大的数据。 !

Project 2: Developmental Programming & Aging Interactions in Primate CV Function ABSTRACT Studying aging in baboons can produce useful information to improve our understanding of aging processes in humans. Systemic cardiovascular (CV) measures, especially cardiac MRI assessments of heart function and structure, will be evaluated along with heart tissue analyses from our fetal and life course archives and CV measurements taken on the same animals during regular living situations to evaluate the CV system in the baboon with aging. The research plan includes studying how stresses on individuals early in life, while still in the womb, will modify the normal aging of the heart in the long term. This research will be carried out by characterizing parameters derived from MRI imaging studies (so called imaging biomarkers) and comparing them with each animal's phenotype, composed of functional, structural and molecular biology measurements, that can be used to predict aging-related changes. Parameters to be measured in the 96 baboons (6-18 years; human ~20-70 years) will characterize left and right ventricular function, aortic distensibility, myocardial extracellular volume, cardiac steatosis, myofilament protein expression, heart rate variability, baroreceptor response and circulating microRNA's. In all groups, we study equal numbers of males and female. These measurements will be carried out for all three aims. In Aim 1 normal life course baboons (N=48) will be studied to establish normative values and serve as age-matched controls for groups studied in subsequent aims. In all animals, we shall correlate data obtained with microarray data, tissue biopsied and system metabolic data to MRI measures of myocardial aging changes. In Aim 2 offspring (F1) of mothers, subjected to moderate (30%) caloric restriction in pregnancy and lactation (N=16), will be studied as well as offspring of obese mothers (OM) fed a high-fat, high-fructose diet during pregnancy (N=16). Studying baboons with these conditions will help differentiate changes due to direct effects on myocardial structure and function versus secondary effects on myocardium due to normal aging. In Aim 3, we shall determine whether the aging trajectory is altered in a subset (N=16), using cortisol replacement intervention (CRI) challenge. We shall use the same methods on all animals in all conditions to evaluate changes in cardiovascular function that are attributed to age-related processes. Importantly, the same animals whose CV parameters are being evaluated in this project (Project 2) are also being studied across the other projects for neuroendocrine, brain and behavioral function (Project 1), and metabolic aging (Project 3). Since the 01 submission we can report five papers published on cardiometabolic effects in the baboon model: three published in J Physiology, one in J Devel Origins Health Dis and one in Int J Obes (Lond). Response to review: We respond to the major named weaknesses, i.e. the diet, lack of fetal approaches, and outline the value of our archives now we do not perform euthanasia at the IRG's request. We show how our effect sizes are high and our subject numbers are at the very highest end of any on nonhuman primate providing good significance in the past and ensure robust data.! !