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

项目 2：开发性编程

• 批准号: 10450802
• 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 2023-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450802
• 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; cardiac magnetic resonance imaging; 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：灵长类简历功能中发育规划与年龄的交互作用 摘要 研究狒狒的衰老可以产生有用的信息，以提高我们对 人类。全身心血管(CV)测量，特别是心脏MRI对心功能和 结构，将与我们的胎儿和生命过程档案和简历中的心脏组织分析一起评估 在正常生活条件下对相同动物进行测量，以评估 随着年龄的增长而出现的狒狒。这项研究计划包括研究个体在生命早期如何承受压力。 从长远来看，子宫将改变心脏的正常老化。这项研究将由以下人员进行 从磁共振成像研究(所谓的成像生物标记物)获得的参数的表征和比较 由功能、结构和分子生物学测量组成的每种动物的表型， 可以用来预测与衰老相关的变化。对96只(6-18岁； 人~20-70岁)将表征左、右心功能、主动脉扩张性、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 反应和循环中的microRNA。在所有的组中，我们研究了相同数量的男性和女性。这些 将对所有三个目标进行测量。在目标1中，将研究正常生活史的狒狒(N=48) 为后续目标中研究的人群建立规范的价值观并作为年龄匹配的对照。总而言之， 动物，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关联起来 MRI测量心肌老化的变化。在目标2个母亲的后代(F1)中，患有中度(30%) 妊娠和哺乳期的热量限制(N=16)以及肥胖母亲(OM)的后代将被研究 妊娠期间喂食高脂肪、高果糖饮食(N=16)。研究具有这些条件的狒狒将会有所帮助 区分直接影响心肌结构和功能的改变与继发性影响 正常衰老所致的心肌。在目标3中，我们将确定老化轨迹是否在 子组(N=16)，使用皮质醇替代干预(CRI)挑战。我们将对所有人使用相同的方法 在所有条件下评估与年龄相关的心血管功能的变化 流程。重要的是，在本项目中正在评估其CV参数的相同动物(项目2) 也在研究神经内分泌、大脑和行为功能的其他项目(项目1)， 和代谢老化(项目3)。自01年提交以来，我们可以报告发表在 狒狒模型的心脏代谢效应：三篇发表在《生理学杂志》上，一篇发表在《J Devel Origins Health Dis》杂志上 一个在Int J OBEs(Lond)。对评审的回应：我们回应了被命名的主要弱点，即 饮食，缺乏胎儿途径，并概述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果规模是如何很高的，我们的受试者数量是在 任何关于非人类灵长类动物的数据都提供了良好的过去意义，并确保了可靠的数据。 好了！