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

项目1：灵长类大脑和糖皮质激素的发育编程和衰老相互作用 功能 主要PI：Peter Nathanielsz;多名PI：Cun Li、Peter Fox 摘要 需要受控的转化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（如血流和代谢）的相互作用影响 大脑老化和认知能力下降。证据支持早期血液GC变化和活动以及其他 衰老的前因Barker编程假设陈述了对关键挑战的反应。 发育时间窗改变发育轨迹，对表型具有持续影响。 初步数据。我们1）证实狒狒血浆皮质醇从6岁开始线性下降（人类~ 15岁）， 显示室旁核（PVN）加压素下降，GC受体（GR）增加， 跌倒的机制（反馈增加和PVN驱动减少）; 2）外周皮质醇产生;以及 3)GR和血流随年龄变化。 场所1.衰老的前因在丘脑-下丘脑-垂体（HHPA）轴的早期就存在， 大脑功能和行为2a.中度围产期全面营养减少诱导的IUGR改变HHPA，脑 结构和功能，以及行为，在IUGR后代（F1）衰老生物标志物的变化中明显， 对照组接受正常围产期营养。2b.围产期的母亲肥胖（MO）会改变HHPA， 大脑结构和功能，以及行为，在MO F1与对照组相比， 接受正常的围产期营养2c.从13岁开始皮质醇替代以维持皮质醇在5岁水平增加 HHPA、大脑和行为老化率，在HHPA和大脑相关老化生物标志物的变化中明显 vs.对照3.将规范的生命过程观察对照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的关键机制的见解。数据 将提供信息翻译给人类，以预测与年龄相关的机制， 减少健康寿命，使人类衰老的标记和干预措施的发展成为可能 Approach.我们研究了96只狒狒的24-68%的生命历程，平等的男性和女性。组：1.正常 生命历程; 2.全球30%的减食母亲IUGR（F1）; 3. F1的过度营养，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，以将表型与细胞途径相关联。没有狒狒 被安乐死我们将我们的胎儿和成人组织档案与体内研究相结合。创新我们提出了一个 新的框架，以了解基于编程老化相互作用的老化。环境用我们的资金 我们建造了室外的饲养设施，并聚集了96只狒狒。非人类灵长类动物（NHP） 全球资源（见字母）。研究者在老化和编程NHP研究方面经验丰富。新 福克斯博士为这个项目带来了脑成像和鲑鱼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.