Project 3: Developmental programming-aging interactions in primate metabolism

项目 3：灵长类动物新陈代谢中的发育规划-衰老相互作用

• 批准号: 10201489
• 负责人: Laura A Cox
• 金额: $ 26.61万
• 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/10201489
• 关键词: Address; Adult; Affect; Age; Aging; Animals; Bioenergetics; Blood; Brain; Caloric Restriction; Cardiovascular Diseases; Cells; Characteristics; Cholesterol; Cholesterol Homeostasis; Chronic; Clinical; Data; Development; Diabetes Mellitus; Diet; Dietary Cholesterol; Dietary Fats; Discipline of Nursing; Dyslipidemias; Early Diagnosis; Early Intervention; Elderly; Exposure to; Fatty acid glycerol esters; Fetal Development; Fetal Growth Retardation; Financial compensation; Fructose; Gene Expression Profiling; Goals; Health; Heart; Heart Diseases; Hepatic; High Fat Diet; Human; Hydrocortisone; Image; Individual; Insulin Resistance; Intake; Intervention; Life; Life Cycle Stages; Life Expectancy; Lipids; Liver; Liver diseases; Measurement; Measures; Metabolic; Metabolic Control; Metabolic dysfunction; Metabolism; Methods; Modeling; Molecular; Molecular Biology; Molecular Profiling; Mothers; Myocardial Infarction; Nutrient; Obesity; Papio; Papio hamadryas; Pathway interactions; Perinatal; Physiological; Plasma; Pregnancy; Primates; Process; Proteomics; Puberty; Regulatory Pathway; Skeletal Muscle; Stress; Stroke; Time; Tissues; Translational Research; Uterus; age related; body system; carbohydrate metabolism; clinically relevant; cohort; comorbidity; early onset; experimental group; falls; feeding; healthspan; imaging approach; in utero; innovation; insight; lipid metabolism; lipidomics; liver biopsy; maternal obesity; metabolic rate; metabolomics; middle age; model development; multiple omics; nonhuman primate; normal aging; novel; novel marker; offspring; predictive marker; predictive signature; prevent; protein expression; therapy development; transcriptomics; young adult

ABSTRACT As humans age, changes affecting nutrient utilization and storage often result in health complications, leading to obesity, diabetes mellitus (DM), cardiovascular disease (CVD) and hepatic complications. These health complications are more prominent with earlier onset when individuals were exposed to maternal obesity (MO) or reduced nutrients during their own fetal development resulting in intra-uterine growth restriction (IUGR). The baboon is a well-characterized nonhuman primate (NHP) model to study human dyslipidemia and other metabolic abnormalities such as insulin resistance and DM. Age-related co-morbidities develop in baboons as in humans. We have developed a unique colony normal life course (NLC), IUGR and MO baboons. Our scientific premises are: 1. Aging-related metabolic changes can be detected early in life. 2. Interactions between developmental programming and aging are major determinants of metabolic control and energy management. 3. Normative data and results from interventions addressing mechanisms of programming and aging in NHP models are essential for translation of research findings to humans to develop therapies to extend health span. We hypothesize that: Characteristic molecular signatures are predictive of metabolic changes caused by perinatal programming (MO, IUGR, and cortisol replacement intervention (CRI) accelerates age-related metabolic complications. We have 3 aims to address this hypothesis: Aim 1: Characterize NLC aging in baboons ranging from young adult to middle-age adult (6-148 years; human equivalent 18-90 years). We will use integrated omic approaches with cellular and physiological measurements to quantify normal aging-related changes in liver, skeletal muscle, and blood. Aim 2: Determine how in utero stresses impact metabolic aging. We will measure parameters described in Aim 1 in IUGR and MO baboons. Aim 3: Determine whether CRI alters the trajectory of metabolic changes that occur with age. We will administer cortisol to NLC baboons for 4 years to determine whether CRI results in age-related metabolic dysfunction. Project 3 is synergistic with integration of our findings and other organ systems (Project 1 – brain; Project 2 – heart and vessels) towards the U19 goal of deriving a comprehensive model for development and prediction of age-related health complications using our unique baboon models, identify predictive molecular signatures, and explore interventions to delay metabolic aging. Project 3 is innovative by integrating metabolic challenges, physiological measures, and cell bioenergetics with comprehensive omic analyses to construct detailed molecular networks that change in normal aging in metabolic tissues and are impacted by in utero stress and cortisol replacement intervention.

抽象的 随着人类年龄的增长，影响营养利用和储存的变化往往会导致健康并发症，导致 肥胖、糖尿病 (DM)、心血管疾病 (CVD) 和肝脏并发症。 当个体患有孕产妇肥胖 (MO) 时，并发症越早发病越突出 或在胎儿发育过程中营养减少，导致子宫内生长受限（IUGR）。 狒狒是一种特征明确的非人类灵长类动物 (NHP) 模型，用于研究人类血脂异常和其他疾病 狒狒会出现胰岛素抵抗和糖尿病等代谢异常。 我们开发了独特的群体正常生命历程（NLC）、IUGR 和 MO 我们的狒狒。 科学前提是： 1. 可以在生命早期检测到与衰老相关的代谢变化。 2. 相互作用。 发育规划和衰老之间的关系是代谢控制和能量的主要决定因素 3. 涉及规划和管理机制的干预措施的规范性数据和结果。 NHP 模型中的衰老对于将研究成果转化为人类以开发治疗方法至关重要 我们发现：特征分子特征可以预测代谢。 围产期规划引起的变化（MO、IUGR 和皮质醇替代干预 (CRI)） 加速与年龄相关的代谢并发症 我们有 3 个目标来解决这一假设： 目标 1： 描述狒狒从青年到中年（6-148 岁；人类）的 NLC 衰老特征 相当于 18-90 岁）我们将使用细胞和生理学的综合组学方法。 测量以量化肝脏、骨骼肌和血液中与衰老相关的正常变化目标 2： 确定子宫内压力如何影响代谢衰老我们将测量目标 1 中描述的参数。 目标 3：确定 CRI 是否改变了代谢变化的轨迹。 我们将给 NLC 狒狒注射皮质醇 4 年，以确定 CRI 是否会导致 项目 3 与我们的发现和其他器官的整合具有协同作用。 系统（项目 1 – 大脑；项目 2 – 心脏和血管），以实现 U19 的目标，即获得全面的 使用我们独特的狒狒模型开发和预测与年龄相关的健康并发症的模型， 确定预测分子特征，并探索延缓代谢衰老的干预措施。 通过将代谢挑战、生理测量和细胞生物能量学与 全面的组学分析，构建在正常衰老过程中发生变化的详细分子网络 代谢组织并受到子宫内压力和皮质醇替代干预的影响。