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 CV 功能的发育编程和衰老相互作用 抽象的 研究狒狒的衰老可以提供有用的信息，以提高我们对狒狒衰老过程的理解 人类。全身心血管 (CV) 测量，尤其是心脏 MRI 评估心脏功能和 结构，将与我们的胎儿和生命历程档案以及简历中的心脏组织分析一起进行评估 在正常生活情况下对同一动物进行测量，以评估 CV 系统 狒狒随着衰老。该研究计划包括研究个体在生命早期和成年期间的压力如何 从长远来看，在子宫内，将改变心脏的正常老化。这项研究将由 表征源自 MRI 成像研究的参数（所谓的成像生物标志物）并进行比较 它们具有每种动物的表型，由功能、结构和分子生物学测量组成， 可用于预测与衰老相关的变化。 96 只狒狒（6-18 岁； 人类~20-70岁）将表征左心室和右心室功能、主动脉扩张性、心肌 细胞外容量、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 microRNA。在所有组中，我们研究的男性和女性人数相同。这些 将对所有三个目标进行测量。在目标 1 中，将研究狒狒 (N=48) 的正常生命历程 建立规范值并作为后续目标中研究群体的年龄匹配对照。总共 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 测量心肌老化变化。在目标 2 中，母亲的后代 (F1) 受到中等程度 (30%) 的影响 怀孕和哺乳期的热量限制（N = 16）以及肥胖母亲的后代（OM）将被研究 怀孕期间喂养高脂肪、高果糖饮食（N=16）。研究具有这些条件的狒狒将有所帮助 区分由于对心肌结构和功能的直接影响引起的变化与对心肌结构和功能的继发影响 心肌由于正常老化。在目标 3 中，我们将确定老化轨迹是否在以下情况发生改变： 子集（N=16），使用皮质醇替代干预（CRI）挑战。我们将对所有的使用相同的方法 在所有条件下对动物进行评估，以评估与年龄相关的心血管功能变化 流程。重要的是，本项目（项目 2）中正在评估其 CV 参数的相同动物 还在神经内分泌、大脑和行为功能的其他项目中进行研究（项目 1）， 和代谢衰老（项目 3）。自 01 提交以来，我们可以报告发表在 狒狒模型中的心脏代谢效应：三篇发表在《J Physiology》杂志上，一篇发表在《J Devel Origins Health Dis》上 以及 Int J Obes（伦敦）的一名。对审查的回应：我们对主要的指定弱点作出回应，即 饮食，缺乏胎儿方法，并概述我们档案的价值，现在我们不在现场实施安乐死 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如何处于最高端的 任何关于非人类灵长类动物的研究在过去都提供了良好的意义并确保了可靠的数据。 ！