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.

抽象的具体目标/意义。在我们特殊的狒狒非人类灵长类动物（NHP）中开发编程和衰老，我们使用分类组和纵向，生活课程方法评估交互式编程机制。开发节目可以定义为对改变生活课程表型的关键发展时间窗口中对挑战的反应。前提/假设。 1。在海马 - - 海波丘脑 - 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。编程互动是生活课程HHPA，大脑，行为，CVS和代谢健康跨度。 3。将正常的，生命课程观察控制数据与三个数据进行比较改变衰老轨迹的干预措施为关键衰老机制和细胞途径以及转化为人类所需的信息，以预测与年龄相关的机制增加或减少健康跨度。发现能够开发标记和人类衰老中的有益干预措施。项目-1。HHPAA，大脑和行为。 2：CVS功能。 3：代谢。核心 - A：行政； B：动物; C：基因组学； D：MRI； E：样本和数据管理。协同作用：所有组件研究全部96 具有体内MRI和系绳研究以及体外组织学，细胞培养和分子方法的动物。我们研究96个狒狒在4组中，在6 - 17年（y）时相等的男性和女性（人类等效〜18-68y; 24– 占人生课程的68％）。组：1。48正常的生活课程控制（NLC）； 2。16iugr后代（F1）中度营养不良的母亲； 3。16F1的肥胖母亲； 4。在16岁的12-17岁时我们夹住血浆皮质醇达到正常水平。 NLC和干预措施中老化机制的比较关于生命过程的信息，整个动物和细胞机制通过编程 - 衰老相互作用所修饰。新的初步数据。我们提供了增加皮质醇和加速大脑，简历和加速的新证据 IUGR代谢衰老。对16-143 PAR的响应能力老化研究（U19）。我们解决了要求的“大规模纵向观察研究…… 分子，遗传，机械数据和干预措施的多种结果……衰老的动物模型相关条件……阐明机制的多个终点。”调查人员来自多个机构并在衰老研究和编程中共同努力并完成了大型NIH P01，R24，P51。我们在全球共享资源。创新。生活课程NHP研究很少见。我们组装了独特的队列，并为这些研究建立了我们自己的定制设施。我们现在1。安乐死，可以在这些队列上进一步申请； 2。将U19在体内和体外数据结合在一起来自我们广泛胎儿（130个胎儿）和产后档案的组织学和分子数据（120名成年人出生至25岁）从子宫到坟墓产生新的机械编程和老化框架。