Womb to Tomb: Developmental Programming and Aging Interactions in Primates

从子宫到坟墓：灵长类动物的发育编程和衰老相互作用

• 批准号: 10450795
• 负责人: GEOFFREY DAVID CLARKE
• 金额: $ 150.55万
• 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/10450795
• 关键词: Address; Adipose tissue; Adrenal Glands; Adult; Age; Aging; Animal Model; Animals; Archives; Area; Behavior; Biological Markers; Biopsy; Birth; Body Weight decreased; Brain; Brain imaging; Calories; Cardiac; Cardiovascular Physiology; Cardiovascular system; Categories; Cell Aging; Cell Culture Techniques; Closure by clamp; Complex; Custom; DNA Maintenance; Data; Development; Epigenetic Process; Etiology; Female; Fetal Growth Retardation; Fetus; Functional Magnetic Resonance Imaging; Genetic; Genomics; Health; Heart; Hippocampus (Brain); Histologic; Human; Hydrocortisone; In Vitro; Institution; Intervention; Lactation; Life; Life Cycle Stages; Liver; Longitudinal observational study; Magnetic Resonance Imaging; Matched Group; Metabolic; Metabolism; Modeling; Molecular; Molecular Genetics; Monoclonal Antibody R24; Mothers; Neonatal; Nutrient; Obesity; Organ; Organism; Outcome; Pancreas; Papio; Pathway interactions; Perinatal; Phenotype; Pituitary Gland; Pituitary-Adrenal System; Plasma; Pregnancy; Primates; Process; Proteins; Publications; Publishing; RNA Stability; Research; Research Personnel; Resource Sharing; Sampling; Signal Pathway; Skeletal Muscle; Structure; System; Time; Tissues; United States National Institutes of Health; Uterus; Work; age related; aged; base; brain behavior; brain magnetic resonance imaging; cardiac magnetic resonance imaging; cohort; data management; drinking water; epidemiology study; experience; falls; fetal; healthspan; improved; in vivo; innovation; insight; interest; male; maternal obesity; mother nutrition; multiple datasets; nonhuman primate; novel; novel strategies; nutrition; offspring; perinatal period; postnatal; response; synergism; translation to humans

ABSTRACT Specific aims/significance. In our well-characterized baboon nonhuman primate (NHP) models of developmental programming and aging we use both categorical group and longitudinal, life course approaches to evaluate interactive programming-aging mechanisms. Developmental programming can be defined as responses to challenges in critical developmental time windows that alter life course phenotype. Premises/hypotheses. 1. Aging antecedents are present early in the hippocampal-hypothalamo-pituitary- adrenal (HHPA) axis (HHPAA), brain, and behavior; cardiovascular system (CVS); and metabolism. 2. Programming-aging interactions are major determinants of life course HHPA, brain, behavior, CVS, and metabolic health span. 3. Comparing normative, life course observational control data with data from three interventions that alter aging trajectory provides insights into key aging mechanisms and cellular pathways and information needed for translation to humans to anticipate age-related mechanisms that either increase or decrease health span. Findings enable development of markers and beneficial interventions in human aging. Projects - 1. HHPAA, Brain, and Behavior. 2: CVS Function. 3: Metabolism. Cores - A: Administrative; B: Animal; C: Genomics; D: MRI; E: Samples and Data Management. Synergy: All components study all 96 animals with in vivo MRI and tether studies and in vitro histological, cell culture, and molecular approaches. We study 96 baboons in 4 groups, equal males and females at 6–17 years (y) (human equivalent ~18–68y; 24– 68% of the life course). Groups: 1. 48 normal life course controls (NLC); 2. 16 IUGR offspring (F1) of moderately undernourished mothers; 3. 16 F1 of obese, over-nourished mothers; 4. In 16 at 12–17y we clamp plasma cortisol to normal 5y levels. Comparison of aging mechanisms in NLC and interventions provides information on life course whole animal and cellular mechanisms modified by programming-aging interactions. New preliminary data. We present new evidence of increased cortisol and accelerated brain, CVS, and metabolic aging in IUGR. Responsiveness to PAR-16-143 Complex Integrated Multi-Component Projects in Aging Research (U19). We address requested “Large-scale longitudinal observational studies… integration of multiple outcomes with molecular, genetic, mechanistic data and interventions… animal models for aging- related conditions… multiple endpoints to elucidate mechanisms.” Investigators are from multiple institutions and have worked and published together in aging research and programming and in completing large NIH P01s, R24s, P51s. We share resources worldwide. Innovation. Life course NHP studies are rare. We assembled unique cohorts and built our own custom facility for these studies. We now 1. perform biopsies not euthanasia, enabling further applications on these cohorts; 2. combine U19 in vivo and in vitro data with histological and molecular data from our extensive fetal (130 fetuses) and postnatal archives (120 adults birth to 25y) to produce a new mechanistic programming and aging framework from womb to tomb.

抽象的 具体目标/意义。在我们充分表征的狒狒非人灵长类动物 (NHP) 模型中 发展规划和老龄化我们使用分类群体和纵向生命历程方法 评估交互式编程老化机制。开发性编程可以定义为 对改变生命历程表型的关键发育时间窗口挑战的反应。 前提/假设。 1. 衰老先兆早在海马-下丘脑-垂体- 肾上腺 (HHPA) 轴 (HHPAA)、大脑和行为；心血管系统（CVS）；和新陈代谢。 2. 编程-衰老相互作用是生命历程的主要决定因素 HHPA、大脑、行为、CVS 和 代谢健康跨度。 3. 将规范的生命历程观察控制数据与来自三个方面的数据进行比较 改变衰老轨迹的干预措施提供了对关键衰老机制和细胞途径的见解， 翻译给人类所需的信息，以预测与年龄相关的机制，这些机制要么增加要么 减少健康寿命。研究结果使得人类衰老标记物的开发和有益的干预措施成为可能。 项目 - 1. HHPAA、大脑和行为。 2：CVS功能。 3：新陈代谢。核心 - A：行政；乙： 动物; C：基因组学； D：核磁共振成像； E：样品和数据管理。协同作用：所有组件研究所有 96 个 动物体内 MRI 和系绳研究以及体外组织学、细胞培养和分子方法。我们 研究了 96 只狒狒，分为 4 组，雄性和雌性同等，年龄为 6-17 岁（相当于人类约 18-68 岁；24- 生命历程的 68%）。组别： 1. 48 个正常生命历程对照 (NLC)； 2. 16个IUGR后代（F1） 中度营养不良的母亲； 3. 16 F1 肥胖、营养过度的母亲； 4. 在 16 岁的 12-17 岁时，我们夹紧 血浆皮质醇至正常 5 年水平。 NLC 和干预措施中衰老机制的比较提供了 有关通过编程-衰老相互作用改变的整个动物和细胞生命过程机制的信息。 新的初步数据。我们提出了皮质醇增加和大脑加速、CVS 和加速的新证据 IUGR 中的代谢衰老。对 PAR-16-143 复杂集成多组件项目的响应能力 衰老研究（U19）。我们解决了“大规模纵向观察研究……整合”的要求 分子、遗传、机械数据和干预措施的多重结果……衰老动物模型- 相关条件……多个端点来阐明机制。”调查人员来自多个机构 并在老龄化研究和规划以及完成大型 NIH 方面一起工作并发表文章 P01、R24、P51。我们在全球范围内共享资源。创新。 NHP 生命历程研究很少见。我们 为这些研究组建了独特的队列并建立了我们自己的定制设施。我们现在 1. 不进行活检 安乐死，使这些群体能够得到进一步的应用； 2. 结合U19体内和体外数据 来自我们广泛的胎儿（130 个胎儿）和产后档案（120 个成人出生）的组织学和分子数据 到 25 岁），以产生一个新的机械编程和从子宫到坟墓的衰老框架。