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中的发展编程和衰老相互作用 功能 铅PI：Peter Nathanielsz；多个PI：Cun Li，Peter Fox 抽象的 需要受控的翻译动物研究来确定发展性编程如何 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，影响 大脑衰老和认知能力下降。证据支持早期血液GC的变化和活动以及其他 衰老的先例。 Barker编程假设指出了对批判性特定挑战的反应 发育时间窗口改变了发展轨迹，对表型的持续影响。 初步数据。我们1）确认从6岁开始（人〜15岁）开始的线性狒狒血浆皮质醇跌落和 显示出dipar脑核（PVN）加压素和增加GC受体（GR）的下降，电势 秋季的机制（增加反馈和PVN驱动器减少）； 2）外周皮质醇产生；和 3）GR和血流随老化而变化。 前提。 1。衰老的先例存在于海马 - - 甲状腺 - 垂体（HHPA）轴的早期， 大脑功能和行为。 2a。中等围产期全球营养减少诱导的IUGR改变了HHPA，大脑 与IUGR后代（F1）老化生物标志物的变化相比，结构和功能和行为显而易见 接受正常围产期营养的对照。 2b。围产期的孕产妇肥胖（MO）改变了HHPA， 大脑结构和功能以及行为，在MO F1中的衰老生物标志物的变化中显而易见 接受正常的围产期营养。 2C。皮质醇替代13岁以保持皮质醇在5年水平上增加 HHPA，大脑和衰老的行为率，在HHPA和脑相关的衰老生物标志物的变化中很明显 与控件。 3。将规范，生活课程观察控制数据与干预措施的数据进行比较 Alter衰老轨迹提供了对系统和细胞衰老途径中关键机制的见解。数据 将提供向人类翻译的信息，以预测与年龄相关的机制，这些机制既增加又 减少健康跨度，使标记的发展和人类衰老的干预措施 方法。我们研究了超过24-68％的人生过程，同等男性和女性的96次狒狒。组：1。正常 生活课程； 2。30％全球食品减少母亲的IUGR（F1）； 3。肥胖的母亲的f1； 4。 皮质醇替代干预措施从13y开始，以将狒狒的皮质醇保持在5岁旧水平5年 解决皮质醇调节机制。我们进行清醒，系绳研究，24h节奏，HHPA抑制 以及刺激，MRI，脑组织学和认知测试，将表型与细胞途径相关联。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。我们提出了一个 基于编程的互动来理解老化的新框架。环境。有了我们的资金， 我们建立了室外持有设施，并组装了96次狒狒。我们共享非人类灵长类动物（NHP） 全球资源（请参阅字母）。研究人员在衰老和编程NHP研究方面经验丰富。新的 对于这个项目，福克斯博士带来了大脑成像和鲑鱼博士强大的细胞培养方法。