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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在我们精心表征的狒狒非人类灵长类动物 (NHP) 模型中的具体目标/意义。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。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. 衰老先兆存在于海马-下丘脑-垂体-中。肾上腺（HHPA）轴（HHPAA）、心血管系统（CVS）和新陈代谢；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 3. 将正常的生命历程观察控制数据与来自三个的数据进行比较。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研究结果使得人类衰老的标记物和有益干预措施的开发成为可能。项目 - 1. HHPAA、大脑和行为 2：CVS 功能 3：新陈代谢。动物；C：基因组学；D：MRI；E：样本和数据管理：所有组件研究全部 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。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： 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 12-17 岁时，我们夹紧血浆皮质醇与正常 5 年水平的比较提供了 NLC 和干预措施中的衰老机制。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。我们提供了新的初步数据，证明皮质醇增加和大脑加速、CVS 和 IUGR 中的代谢衰老对 PAR-16-143 复杂综合多成分项目的反应。老龄化研究（U19）。我们解决了“大规模纵向观察研究……整合”的问题。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……阐明机制的多个终点。” 并在大型 NIH 的老龄化研究和编程领域共同工作并发表文章 P01s、R24s、P51s。我们在全球范围内共享生命历程 NHP 研究。我们现在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。 1. 不进行活检。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胎儿广泛（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），以产生新的机械编程和从子宫到坟墓的老化框架。