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的发育规划和衰老交互作用 功能 主演PI：Peter Nathanielsz；多个PI：李存利、Peter Fox 摘要 需要进行受控的翻译动物研究来确定发育编程-衰老 糖皮质激素(GC-皮质醇)和其他机制的相互作用，如血流和新陈代谢，影响 大脑老化和认知能力下降。证据支持早期血液中GC的变化和活动以及其他 衰老的前驱因素。巴克编程假说陈述了对关键问题中特定挑战的反应 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)证实了从6岁(人类~15岁)开始的恒河猴血浆皮质醇的线性下降 显示室旁核(PVN)加压素下降，GC受体(GR)电位升高 跌倒的机制(反馈增加和PVN驱动减少)；2)外周皮质醇的产生；以及 3)GR和血流量随年龄增长而变化。 房舍。1.衰老先兆早期存在于海马-下丘脑-垂体(HHPA)轴， 大脑功能和行为。2A。围产期中度营养减少性IUGR改变HHPA、脑 IUGR后代(F1)衰老生物标志物的变化明显的结构和功能，以及行为 对照组接受正常围产期营养。2B。围产期母亲肥胖(MO)改变HHPA， 大脑结构和功能，以及行为，在MO F1与对照组的老化生物标志物的变化中明显 接受正常的围产期营养。2C。从13年开始更换皮质醇以将皮质醇维持在5年水平增加 HHPA、脑和行为衰老的速度，明显表现在HHPA和脑相关衰老生物标志物的变化上 与控制的对比。3.比较规范的生命周期观察控制数据与干预措施的数据 改变衰老轨迹提供了对系统和细胞衰老途径中的关键机制的见解。数据 将为人类提供翻译信息，以预测与年龄相关的机制，这些机制既增加了 缩短健康寿命，使人类老龄化标志物和干预措施的发展成为可能 接近。我们在24-68%的生命周期中研究了96只狒狒，雌雄不一。分组：1.正常 生命进程；2.全球30%食物减少母亲的IUGR(F1)；3.营养过度、肥胖母亲的F1； 从13年开始进行皮质醇替代干预，将狒狒的皮质醇水平维持在5岁以下5年至 阐述皮质醇调节机制。我们进行清醒、系绳研究、24小时节律、HHPA抑制 以及刺激、核磁共振、脑组织学和认知测试，以将表型与细胞通路联系起来。不会有企鹅 都被安乐死了。我们将胎儿和成人组织档案与活体研究相结合。创新。我们提出了一个 基于编程-衰老交互作用理解衰老的新框架。环境用我们的资金， 我们建造了我们的户外收容设施，并组装了96只狒狒。我们共享非人灵长类(NHP) 全球资源(见信函)。研究人员在老化和规划NHP研究方面经验丰富。新的 在这个项目中，福克斯博士带来了脑成像和萨蒙博士强大的细胞培养方法。

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.