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: 10201479
• 负责人: GEOFFREY DAVID CLARKE
• 金额: $ 263.87万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201479
• 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; 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.

摘要 明确的目标/意义。在我们很好地描述了狒狒非人灵长类(NHP)模型中 发展规划和老龄化我们既使用范畴组方法，也使用纵向生命过程方法 评估互动编程老化机制。发展规划可定义为 对改变生命过程表型的关键发育时间窗口中的挑战的反应。 前提/假设。1.衰老先兆出现在早期的海马体-下丘脑-垂体部- 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-衰老交互作用是生命过程HHPA、大脑、行为、CVS和 新陈代谢健康跨度。3.比较规范的、生命周期观测控制数据与三年来的数据 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 缩短健康持续时间。这些发现有助于开发人类衰老的标志物和有益的干预措施。 项目-1.HHPAA、大脑和行为。2：CVS功能。3：代谢。核心-A：管理；B： 动物；C：基因组学；D：核磁共振；E：样本和数据管理。协同：所有组件研究所有96个 动物体内核磁共振和系链研究以及体外组织学、细胞培养和分子方法。我们 研究4组96只狒狒，雌雄各半，年龄6-17岁(相当于人类18-68岁；24-24岁) 生命历程的68%)。对照组(NLC)48只；IUGR子代(F1)16只。 中度营养不良的母亲；3.16F1的肥胖、过度营养的母亲；4.在16年12-17岁时我们夹住 血浆皮质醇恢复到正常的5年水平。NLC和干预措施中衰老机制的比较 关于生命过程、整个动物和细胞机制的信息，通过编程-衰老相互作用进行修改。 新的初步数据。我们提出了皮质醇增加和脑血管痉挛加速的新证据。 宫内发育迟缓的代谢性衰老。对PAR-16-143复杂综合多组件项目的响应 老龄化研究(U19)。我们解决了请求的“大规模纵向观察性研究…”集成 分子、遗传、机制数据和干预的多重结果…衰老的动物模型- 相关条件…多个端点来阐明机制。调查人员来自多个机构 在老龄化研究和编程以及完成大型NIH的过程中共同工作和出版 P01s、R24s、P51s。我们在全球共享资源。创新。生命周期NHP研究很少见。我们 聚集了独特的队列，并为这些研究建立了我们自己的定制设施。我们现在不做活组织检查 安乐死，使这些队列的进一步应用成为可能；2.将U19体内和体外数据与 来自我们广泛的胎儿(130个胎儿)和出生后档案(120个成人出生)的组织和分子数据 到25y)，以产生一个新的机械式编程和从子宫到坟墓的老化框架。