`Core B: Animal Core

`核心B：动物核心

基本信息

批准号：
10201482
负责人：
Christopher Yeh Chen
金额：
$ 127.58万
依托单位：
UNIVERSITY OF WYOMING
依托单位国家：
美国
项目类别：
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/10201482
关键词：
3 year old Address Adopted Adrenal Glands Age Aging Animal Welfare Animals Archives Awareness Behavior Betamethasone Biological Markers Birth Body Weight decreased Brain Calories Cardiac Cardiovascular system Cell Aging Characteristics Corticotropin Data Development Diagnostic Doctor of Philosophy Eating Endocrine Environment Euthanasia Event Failure Female Fetal Growth Fetal Growth Retardation Fetus Fibroblasts Food Genetic Glucocorticoids Goals Hippocampus (Brain)Housing Human Hydrocortisone In Vitro Individual Intake Intervention Knowledge Lactation Lead Learning Life Life Cycle Stages Life Expectancy Longevity Magnetic Resonance Imaging Maintenance Malnutrition Measures Metabolic Metabolism Modeling Molecular Mothers Neonatal Neuropsychological Tests Nutrient Organ Paper Papio Pathway interactions Patients Perinatal Phenotype Physiological Pituitary Gland Pituitary-Adrenal System Population Pregnancy Primates Procedures Publications Published Comment Publishing Randomized Research Resources Risk Role Skin Social Dominance Stress Tests Structure Surrogate Mothers System Techniques Testing Training Uterus Variant Vertebrates Weaning Weight age related biological systems brain behavior data integration experience falls feeding fetal frailty healthspan in vivo indexing insight male maternal obesity mortality nonhuman primate nutrition offspring perinatal period postnatal pregnancy failure pregnant prevent response sex social sound synergism translation to humans

项目摘要

Core B: Animal Core – Lead PI: Cun Li, MD; Multiple PI: Peter W Nathanielsz, MD, PhD Animal Core Abstract: Significance/Justification of nonhuman primate studies. Extensive separate aging and programming research exists but few studies address programming-aging interactions and none in nonhuman primates (NHP) other than our own recent publications. Baboons are the closest practical experimental species to humans. Knowledge gained will help develop new interventions to increase health span even in early life and permit diagnostic approaches to identify patients at risk of accelerated aging. Premises/hypotheses. 1. Antecedents of aging exist early in hippocampal-hypothalamo-pituitary-adrenal (HHPA) axis, brain structure and function, and behavior; cardiovascular system (CVS); metabolic biomarkers, and associated genetics. 2. Programming-aging interactions are major determinants of life course health span. 2a. Moderate perinatal maternal nutrient reduction alters HHPA axis, brain and behavior, CVS, and metabolic function evident in accelerated changes in aging biomarkers in their IUGR offspring (F1) compared to normal life course (NLC) controls receiving normal perinatal nutrition. 2b. Maternal obesity (MO) in the perinatal period alters function in the HHPA axis, brain and behavior, CVS, and metabolism evident in accelerated changes in aging biomarkers compared to NLC receiving normal perinatal nutrition. 2c. Cortisol replacement intervention to prevent the life course cortisol fall increases the rate of aging in the systems studied evident in accelerated changes in aging biomarkers compared to NLC baboons in which the NLC cortisol falls. 3. Comparing NLC control data with data from three interventions that alter the aging trajectory provides insights into key mechanisms in systems and cellular aging pathways for translation to humans to anticipate age-related mechanisms that decrease health span enabling development of human aging markers and interventions. Our studies will also provide basc information on normal organ function not obtainable in humans. Approach. We study equal male and female baboons in all groups using in vivo techniques – tether, CVS, endocrine, metabolic approaches, MRI, and in vitro studies on skin fibroblasts. Synergy. All 96 baboons undergo the same procedures allowing data integration across biological systems. Response to IRG observed weaknesses. Specifically, we removed redundancies and addressed colony lifespan variations - our goal is to start from an early age to study aging to obtain a data continuum as animals age. We describe programming models in more detail. Because of lack of enthusiasm and IRG criticisms we removed the maternal glucocorticoid group. We no longer conduct euthanasia on any animals. In the General Overview we justify the title Womb to Tomb with plans to incorporate published fetal data and new data from our fetal and postnatal archives. We present our plans to share unique resources worldwide and clearly state that all animals that have undergone a treatment have age-matched NLC group controls. The human intruder test replaces the isolation stress test. Tether maintenance is described in detail. Animal Welfare. We have experience with all procedures for over 32y.

核心 B：动物核心 – 首席 PI：Cun Li，医学博士；多个 PI：Peter W Nathanielsz，MD、PhD；动物核心摘要：非人类灵长类动物研究的意义/合理性。存在研究，但很少有研究涉及编程与衰老的相互作用，而且没有针对非人类灵长类动物的研究（NHP）除了我们自己最近发表的文章外，狒狒是最接近实用的实验物种。获得的知识将有助于开发新的干预措施，以延长生命早期的健康寿命。允许诊断方法来识别有加速衰老风险的患者。衰老的先兆存在于海马-下丘脑-垂体-肾上腺（HHPA）轴、大脑结构中和功能和行为；心血管系统（CVS）；代谢生物标志物和相关遗传学。编程与衰老的相互作用是生命历程健康寿命的主要决定因素2a。母体营养减少会改变 HHPA 轴、大脑和行为、CVS 和代谢功能，这在与正常生命历程 (NLC) 相比，IUGR 后代 (F1) 的衰老生物标志物加速变化 2b. 接受正常围产期营养的母亲肥胖（MO）会改变围产期的功能。 HHPA 轴、大脑和行为、CVS 和新陈代谢在衰老生物标志物的加速变化中表现明显与接受正常围产期营养的 NLC 相比，皮质醇替代干预可预防生命危险。皮质醇下降当然会增加所研究系统的衰老速度，这在加速衰老变化中很明显生物标志物与 NLC 皮质醇下降的 NLC 狒狒进行比较 3. 将 NLC 对照数据与 NLC 对照数据进行比较。来自改变衰老轨迹的三种干预措施的数据提供了对系统关键机制的见解和细胞衰老途径转化为人类，以预测减少的年龄相关机制我们的研究还将提供促进人类衰老标记和干预措施发展的健康跨度。我们研究了在人类中无法获得的关于正常器官功能的基本信息。使用体内技术（系绳、CVS、内分泌、代谢方法、MRI、以及对皮肤成纤维细胞的体外研究，所有 96 只狒狒都经历了相同的程序，获得了数据。具体来说，我们消除了 IRG 观察到的弱点。冗余和解决群体寿命差异 - 我们的目标是从很小的时候开始研究衰老由于缺乏关于动物年龄的数据连续体，我们更详细地描述了编程模型。由于热情和 IRG 的批评，我们取消了孕产妇糖皮质激素组，我们不再进行。在概述中，我们证明了“从子宫到坟墓”这一标题的合理性，并计划：我们将已发布的胎儿数据以及来自胎儿和产后档案的新数据纳入其中。共享全球独特的资源，并明确声明所有接受过治疗的动物都已年龄匹配的 NLC 组对照。人类入侵者测试取代了隔离压力测试。动物福利方面的维护有超过 32 年的经验。