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: 10450803
• 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 2023-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450803
• 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 随着人类的年龄，影响养分利用和储存的变化通常会导致健康并发症，导致 对于肥胖症，糖尿病（DM），心血管疾病（CVD）和肝脏并发症。这些健康 当个体暴露于孕产妇肥胖症（MO）时，并发症更为突出。 或在自身​​胎儿发育过程中降低营养因素，从而受到了局内生长限制（IUGR）。 狒狒是一种良好的非人类灵长类动物（NHP）模型，研究人类血脂异常和其他 代谢异常，例如胰岛素抵抗和DM。与年龄有关的合并症在狒狒中发展为 在人类中。我们已经开发了独特的殖民地正常生活课程（NLC），IUGR和MO狒狒。我们的 科学前提是：1。与衰老相关的代谢变化可以在生命的早期发现。 2。相互作用 在制定编程和衰老之间是代谢控制和能量的主要确定 管理。 3。规范性数据和干预措施的结果，解决了编程机制和 NHP模型中的衰老对于将研究结果转化为人类以开发疗法至关重要 扩展健康跨度。我们假设：特征性分子特征可预测代谢 围产期编程引起的变化（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个目的是解决这一假设：目标1： 表征NLC衰老的狒狒衰老，从年轻人到中年成年人（6-148岁；人类） 等效18 - 90年）。我们将使用详细的OMIC方法与细胞和生理学 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： 确定子宫内应力如何影响代谢衰老。我们将测量AIM 1中描述的参数 在iugr和mo狒狒中。目标3：确定CRI是否改变了代谢变化的轨迹 随着年龄的增长而发生。我们将向NLC狒狒施用皮质醇4年，以确定CRI是否导致 与年龄有关的代谢功能障碍。项目3与我们的发现和其他器官的整合是协同的 系统（项目1 - 大脑；项目2 - 心脏和船只）​​朝着U19的目标进行全面的目标 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 识别预测性分子特征，并探索干预措施以延迟代谢衰老。项目3是 通过整合代谢挑战，物理措施和细胞生物能学的创新性 全面的OMIC分析以构建详细的分子网络，以改变正常衰老的变化 代谢组织，受子宫胁迫和皮质醇替代干预的影响。