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

项目 2：开发性编程

• 批准号: 10201488
• 负责人: GEOFFREY DAVID CLARKE
• 金额: $ 20.63万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201488
• 关键词: Address; Affect; Age; Aged, 80 and over; Aging; Animal Model; Animals; Archives; Arrhythmia; Autophagocytosis; Behavioral; Biopsy; Blood Vessels; Brain; Caloric Restriction; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Characteristics; Control Groups; Data; Development; Diet; EFRAC; Effectiveness; Elderly; Ensure; Epigenetic Process; Euthanasia; Fatty acid glycerol esters; Female; Fetal Growth Retardation; Fibrosis; Fructose; Future; Genomics; Glucocorticoids; Health; Heart; Heart Diseases; Heart failure; Human; Hydrocortisone; Hyperglycemia; Hypertension; Immune; Impairment; Individual; Insulin Resistance; Intervention; Lactation; Left; Left Ventricular Remodeling; Life; Life Cycle Stages; Light; Liver; Longevity; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Measurement; Measures; Metabolic; Methods; Microfilaments; Microscopic; Modeling; Molecular; Molecular Biology; Mothers; Myocardial; Myocardial dysfunction; Myocardial tissue; Myocardium; Names; Neurosecretory Systems; Oxidative Stress; Paper; Papio; Patients; Pattern; Perinatal; Phenotype; Phylogenetic Analysis; Physiology; Play; Population; Pregnancy; Pressoreceptors; Primates; Process; Publishing; Renin-Angiotensin-Aldosterone System; Reporting; Research; Right Ventricular Function; Savings; Smooth Muscle; Stress; Structure; System; Systolic heart failure; Time; Tissues; United States; Uterus; Ventricular; Ventricular Remodeling; age related; base; cardiometabolism; circulating microRNA; cohort; coronary fibrosis; design; experimental group; extracellular; falls; fetal; functional decline; glucose metabolism; glycemic control; heart function; heart rate variability; hypercholesterolemia; imaging biomarker; imaging study; improved; in utero; in vivo; indexing; individual variation; insight; insulin signaling; lipid metabolism; male; mortality; nonhuman primate; normal aging; obese mothers; offspring; postnatal; protein expression; response; senescence; structural biology; synergism; theories; translational study

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.! !

项目2：灵长类动物简历功能中的发展节目和老化互动 抽象的 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。系统性心血管措施（CV）措施，尤其是心脏功能和心脏MRI评估 结构将与我们的胎儿和生命过程档案中的心脏组织分析一起评估 在常规生活情况下对同一动物进行的测量，以评估CV系统 狒狒衰老。研究计划包括研究生活早期对个人的压力，同时仍在 子宫将长期修改心脏的正常衰老。这项研究将由 表征来自MRI成像研究（所谓的成像生物标志物）的参数并比较 它们与每个动物的表型，由功能，结构和分子生物学测量组成， 可以用来预测与衰老相关的变化。在96个狒狒（6-18岁）中测量的参数； 人类〜20 - 70年）将表征左右心室功能，主动脉膨胀性，心肌 细胞外体积，心脏脂肪变性，肌丝蛋白表达，心率变异性，压力感受器 响应和循环microRNA。在所有小组中，我们研究了相等数量的男性和女性。这些 将对所有三个目标进行测量。在AIM 1正常生命课程狒狒（n = 48）将被研究 建立规范价值并用作随后目标中研究的组的年龄匹配对照。总的来说 动物，我们应将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 心肌老化的MRI测量。在AIM 2后代（F1）的母亲中，受到中等的约束（30％） 妊娠和泌乳的热量限制（n = 16），以及肥胖母亲的后代（OM） 在怀孕期间喂养高脂，高果糖饮食（n = 16）。在这些条件下研究狒狒会有所帮助 由于直接影响心肌结构和功能与次要影响，因此区分了变化 心肌因正常衰老而导致。在AIM 3中，我们将确定在A中是否改变了衰老轨迹 子集（n = 16），使用皮质醇替代干预（CRI）挑战。我们将在所有人上使用相同的方法 在所有条件下的动物，以评估归因于年龄有关的心血管功能的变化 过程。重要的是，在该项目中评估了CV参数的相同动物（项目2） 也在其他项目中研究神经内分泌，大脑和行为功能（项目1）， 和代谢衰老（项目3）。自01提交以来，我们可以报告发表的五篇论文 狒狒模型中的心脏代谢效应：三个在J生理学中发表 一个在Int J Obes（Lond）中。对审查的回应：我们回应了主要的弱点，即 饮食，缺乏胎儿方法，概述了我们的档案的价值，现在我们不在 IRG的要求。我们展示了我们的效果大小如何很高，并且我们的主题数量是最高的 任何关于非人类灵长类动物的人都具有过去的重要意义，并确保了强大的数据。 呢