`Core B: Animal Core

`核心B：动物核心

• 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
• 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

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-主要PI：Cun Li，MD;多名PI：Peter W Nathanielsz，MD，PhD 动物核心摘要： 非人灵长类动物研究的意义/依据。广泛的单独老化和编程 存在研究，但很少有研究涉及编程-衰老相互作用，而且没有在非人类灵长类动物中进行过研究 (NHP)除了我们最近的出版物。狒狒是最接近实际的实验物种， 人类获得的知识将有助于开发新的干预措施，以增加健康寿命，即使在生命早期， 允许诊断方法来识别处于加速老化风险中的患者。前提/假设。1. 大脑皮层-下丘脑-垂体-肾上腺（HHPA）轴、脑结构和脑组织结构存在衰老的早期因素 功能和行为;心血管系统（CVS）;代谢生物标志物和相关遗传学。2. 程序化-老化交互作用是生命历程健康寿命的主要决定因素。2a.中度围产期 母体营养减少改变HHPA轴、大脑和行为、CVS和代谢功能， 与正常生命过程（NLC）相比，IUGR后代（F1）中衰老生物标志物的加速变化 对照组接受正常围产期营养。2b.围产期的母亲肥胖（MO）改变了 HHPA轴、大脑和行为、CVS和代谢在衰老生物标志物的加速变化中明显 与接受正常围产期营养的NLC相比。2c.皮质醇替代干预，以防止生命 皮质醇下降会加快所研究系统的衰老速度，这在加速衰老的变化中是显而易见的 与NLC皮质醇福尔斯下降的NLC狒狒相比，3.将NLC对照数据与 来自三种改变衰老轨迹的干预措施的数据提供了对系统中关键机制的见解 和细胞衰老途径翻译到人类，以预测与年龄相关的机制， 健康跨度使得能够开发人类衰老标记和干预。我们的研究还将提供 人体无法获得的正常器官功能的基本信息。Approach.我们研究平等的男性， 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。协同增效。所有96只狒狒都经历了同样的程序， 跨生物系统的整合。对伊斯兰革命卫队的答复指出了弱点。具体来说，我们删除了 冗余和解决殖民地寿命的变化-我们的目标是从早期开始研究衰老， 随着动物年龄的增长获得数据连续体。我们将更详细地描述编程模型。因为缺乏 热情和IRG的批评，我们删除了母体糖皮质激素组。我们不再进行 对任何动物实施安乐死。在总体概述中，我们证明了标题子宫到坟墓的计划， 结合已发表的胎儿数据和来自我们胎儿和产后档案的新数据。我们将我们的计划提交给 在全球范围内共享独特的资源，并明确声明所有接受治疗的动物都 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。系绳 详细描述了维护。动物福利。我们有超过32年的所有程序的经验。