Project 1: Developmental Programming and Aging Interactions in Primate Brain and Glucocorticoid Function.

项目 1：灵长类动物大脑和糖皮质激素功能的发育规划和衰老相互作用。

• 批准号: 10450801
• 负责人: PETER W. NATHANIELSZ
• 金额: $ 27.74万
• 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/10450801
• 关键词: Acclimatization; Address; Adrenal Glands; Adult; Age; Aging; Anesthetics; Animals; Behavior; Beverages; Biological Markers; Birth; Blood; Blood flow; Body Weight decreased; Body fat; Brain; Brain imaging; Breeding; Calories; Carbohydrates; Cell Aging; Cell Culture Techniques; Cognition; Conscious; Control Groups; Data; Development; Diet; Eating; Environment; Evaluation; Explosion; Failure; Fatty acid glycerol esters; Feedback; Female; Fetal Growth Retardation; Fetus; Food; Foxes; Fructose; Funding; General Anesthesia; Glucocorticoids; Glucose; Goals; Hippocampus (Brain); Histology; Housing; Human; Hydrocortisone; Impaired cognition; Individual; Infusion procedures; Intake; Intervention; Isotopes; Lactation; Lead; Letters; Life; Life Cycle Stages; Longevity; Magnetic Resonance Imaging; Measures; Mediating; Metabolic Clearance Rate; Metabolism; Modeling; Mothers; Neonatal; Nuclear; Nulliparity; Nutrient; Obesity; Outcome; Outcome Study; Paper; Papio; Pathway interactions; Perinatal; Peripheral; Phenotype; Pituitary Gland; Plasma; Pregnancy; Pregnancy Outcome; Primates; Procedures; Production; Publications; Publishing; Randomized; Research Personnel; Resources; Salmon; Skin; Solid; Stress; Structure; Surrogate Mothers; System; Techniques; Time; Uterus; Variant; Vasopressins; Weaning; Weight; Woman; age related; aging brain; awake; base; brain behavior; brain magnetic resonance imaging; cognitive testing; dietary control; drinking water; experience; falls; feeding; fetal; healthspan; in vivo; innovation; insight; male; maternal obesity; mother nutrition; nonhuman primate; nutrition; obese mothers; offspring; perinatal period; pregnant; programs; receptor; reproductive; response; sex; tissue archive; translation to humans

Project 1: Developmental Programming and Aging Interactions in Primate Brain and Glucocorticoid Function Lead PI: Peter Nathanielsz; Multiple PIs: Cun Li, Peter Fox ABSTRACT Controlled translational animal studies are needed to determine how developmental programming-aging interactions by glucocorticoid (GC- cortisol) and other mechanisms, e.g. blood flow and metabolism, influence brain aging and cognitive decline. Evidence supports early blood GC changes and activity and other antecedents of aging. The Barker programming hypothesis states responses to specific challenges in critical developmental time windows alter the developmental trajectory with persistent effects on phenotype. Preliminary data. We 1) confirmed a linear baboon plasma cortisol fall starting at 6y age (human ~15y) and showed a fall in paraventricular nuclear (PVN) vasopressin and increased GC receptor (GR), potential mechanisms for the fall (increased feedback and decreased PVN drive); 2) peripheral cortisol production; and 3) GR and blood flow changes with aging. Premises. 1. Aging antecedents are present early in the hippocampal-hypothalamo-pituitary (HHPA) axis, brain function, and behavior. 2a. Moderate perinatal global nutrient reduction-induced IUGR alters HHPA, brain structure and function, and behavior, evident in changes in IUGR offspring (F1) aging biomarkers compared to controls who received normal perinatal nutrition. 2b. Maternal obesity (MO) in the perinatal period alters HHPA, brain structure and function, and behavior, evident in changes in aging biomarkers in MO F1 vs. controls who received normal perinatal nutrition. 2c. Cortisol replacement from 13y to maintain cortisol at 5y levels increases the HHPA, brain, and behavior rate of aging, evident in changes in HHPA and brain-related aging biomarkers vs. controls. 3. Comparing normative, life course observational control data with data from interventions that alter the aging trajectory provides insights into key mechanisms in systems and cellular aging pathways. Data will provide information for translation to humans to anticipate age-related mechanisms that both increase and decrease health span, enabling development of markers and interventions in human aging Approach. We study 96 baboons over 24-68% of the life course, equal males and females. Groups: 1. Normal life course; 2. IUGR (F1) of 30% globally food reduced mothers; 3. F1 of over-nourished, obese mothers; 4. Cortisol Replacement Intervention beginning at 13y to maintain baboons' cortisol at 5y old levels for 5 years to address cortisol regulated mechanisms. We conduct awake, tether studies, 24h rhythms, HHPA suppression and stimulation, MRI, brain histology, and cognitive tests to relate phenotype to cellular pathways. No baboons are euthanized. We integrate our fetal and adult tissue archives with in vivo studies. Innovation. We propose a new framework to understand aging based on programming-aging interactions. Environment. With our funds, we built our outdoor holding facilities and assembled 96 baboons. We share nonhuman primate (NHP) resources worldwide (see letters). Investigators are experienced in aging and programing NHP studies. New to this Project, Dr. Fox brings brain-imaging and Dr. Salmon powerful cell culture approaches.

项目 1：灵长类动物大脑和糖皮质激素的发育规划和衰老相互作用 功能 首席 PI：Peter Nathanielsz；多个 PI：Cun Li、Peter Fox 抽象的 需要受控的转化动物研究来确定发育程序如何影响衰老 糖皮质激素（GC-皮质醇）和其他机制的相互作用，例如血流和新陈代谢的影响 大脑老化和认知能力下降。有证据支持早期血液 GC 变化和活动等 衰老的前因。巴克编程假设阐述了对关键领域特定挑战的响应 发育时间窗改变发育轨迹，对表型产生持续影响。 初步数据。我们 1) 证实狒狒血浆皮质醇从 6 岁开始呈线性下降（人类约 15 岁），并且 显示室旁核 (PVN) 加压素下降和 GC 受体 (GR) 增加，潜力 跌倒的机制（反馈增加和 PVN 驱动力减少）； 2）外周皮质醇的产生；和 3）GR和血流量随衰老而变化。 前提。 1. 衰老先兆存在于海马-下丘脑-垂体（HHPA）轴的早期， 大脑功能和行为。 2a.中度围产期整体营养减少引起的 IUGR 改变 HHPA、大脑 与对照组相比，IUGR 后代 (F1) 衰老生物标志物的结构、功能和行为变化明显 控制接受正常围产期营养的人。 2b.围产期母亲肥胖 (MO) 会改变 HHPA， MO F1 与对照者的大脑结构和功能以及行为在衰老生物标志物的变化中很明显 接受正常的围产期营养。 2c.为了将皮质醇维持在 5 岁水平，从 13 岁开始补充皮质醇会增加 HHPA、大脑和衰老行为率，HHPA 和大脑相关衰老生物标志物的变化很明显 与控制。 3. 将规范的生命历程观察控制数据与干预措施的数据进行比较 改变衰老轨迹提供了对系统和细胞衰老途径关键机制的见解。数据 将提供翻译给人类的信息，以预测与年龄相关的机制，这些机制会增加和减少 缩短健康寿命，促进人类衰老标记物和干预措施的开发 方法。我们研究了 96 只狒狒，涵盖了 24-68% 的生命历程，雄性和雌性相同。组别： 1. 正常组 生命历程； 2. 全球 30% 食物减少母亲的 IUGR（F1）； 3、F1期营养过度、肥胖的母亲； 4. 从 13 岁开始进行皮质醇替代干预，将狒狒的皮质醇维持在 5 岁水平，持续 5 年 解决皮质醇调节机制。我们进行清醒、系绳研究、24 小时节律、HHPA 抑制 以及刺激、MRI、脑组织学和认知测试，将表型与细胞通路联系起来。没有狒狒 被安乐死。我们将胎儿和成人组织档案与体内研究相结合。创新。我们提出一个 基于编程与老化交互来理解老化的新框架。环境。凭借我们的资金， 我们建造了户外饲养设施并聚集了 96 只狒狒。我们共享非人类灵长类动物 (NHP) 全球资源（见信件）。研究人员在衰老和 NHP 研究方面经验丰富。新的 Fox 博士为该项目带来了脑成像和 Salmon 博士强大的细胞培养方法。