Age Induced Impairment of Nutrient Signaling Results in Bone Loss

年龄引起的营养信号损伤导致骨质流失

• 批准号: 9902273
• 负责人: CARLOS M. ISALES
• 金额: $ 220.89万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902273
• 关键词: Acetylation; Affect; Age; Age-Related Bone Loss; Aging; American; Amino Acids; Award; Bioinformatics; Biological Assay; Biology; Biomechanics; Biometry; Bone Marrow; C57BL/6 Mouse; Cell physiology; Cells; Collaborations; Core Facility; Data; Dietary Intervention; Epigenetic Process; Functional disorder; Funding; Goals; Health Care Costs; Histone Deacetylase; Homing; Human; Impairment; Individual; Intermittent fasting; Knowledge; Kynurenine; Lead; MicroRNAs; Modification; Molecular; Mus; Muscle; Muscular Atrophy; Musculoskeletal; Musculoskeletal Development; Nutrient; Osteoporosis; Outcome; Oxides; Pathway interactions; Pattern; Physiology; Productivity; Protein Deficiency; Proteins; Public Health; Research Personnel; Role; Serum; Services; Signal Pathway; Signal Transduction; Stimulus; Stromal Cell-Derived Factor 1; Stromal Cells; Supplementation; System; Techniques; Testing; Tryptophan; Work; age related; base; bone; bone imaging; bone loss; chemokine; clinical practice; detection of nutrient; epigenetic regulation; exosome; extracellular vesicles; feeding; frailty; improved; innovation; mouse model; novel; programs; regenerative; repository; stem cells

This is a competitive renewal application of our currently funded Program Project (P01) award entitled “Age- induced Impairment of Nutrient Signaling Results in Bone Loss”. Osteoporosis is a major public health problem affecting 44 million Americans. The estimated annual direct health-care cost for osteoporosis totaled $17 billion in 2001 and is rapidly rising. A critical barrier to correcting the problem of frailty and osteoporosis is a poor understanding of how nutrient-related stimuli and epigenetic mechanisms interact to induce bone and muscle loss. Our central hypothesis is that aging alters epigenetic regulatory systems (e.g., miRNA, acetylation) that act through nutrient signaling pathways on stem cells to affect musculoskeletal function. This project will improve scientific knowledge, technical capability, and clinical practice as they relate to age-induced muscle and bone loss by 1) defining specific epigenetic mechanisms that lead to bone and muscle loss with aging and 2) identifying specific nutritional interventions that can reduce or reverse these age-related changes. This is a highly integrated proposal from a group with an established track record of interactions, productivity and collaborations. Four individual projects, focused on epigenetic regulation and nutrient-related stimuli, comprise this application. The proposal also includes three Core facilities that will provide essential support to the Projects: an Administrative Core (Core A) that includes biostatistics and bioinformatics; a Bone Biology Core (Core B), which will provide the bone-specific techniques utilized by all the investigators; and a Bone Stem Cell Core (Core C) that will provide bone-derived cells to all investigators, including mouse and human bone marrow progenitor cells. The project has three specific aims: Aim 1 will test the hypothesis that age-related changes in epigenetic signals alter musculoskeletal stem cell function; Aim 2 will test the hypothesis that specific dietary interventions (e.g., selective amino acid supplementation or intermittent fasting/protein feeding) can reverse age-related changes in epigenetic modifications and promote normal stem cell function; Aim 3 will test the hypothesis that relevant age-related epigenetic modifications identified in our mouse model are translatable to normal human physiology. The long-term impact of this project will be new findings on the epigenetic mechanisms underlying bone and muscle loss with age, and new countermeasures for reducing or reversing musculoskeletal aging.

这是对我们目前资助的计划项目(P01)奖的竞争性续签申请，该奖项名为“年龄- 营养信号的诱导损伤会导致骨丢失。骨质疏松症是一个主要的公共卫生问题 影响到4400万美国人。骨质疏松症每年的直接医疗费用估计为170亿美元。 2001年，并且正在迅速上升。纠正脆弱和骨质疏松症问题的关键障碍是穷人 了解营养相关刺激和表观遗传机制如何相互作用以诱导骨骼和肌肉 损失。我们的中心假设是，衰老改变了表观遗传调节系统(例如，miRNA，乙酰化)， 通过干细胞上的营养信号通路影响肌肉骨骼功能。这个项目将 提高科学知识、技术能力和临床实践，因为它们与年龄诱导的肌肉有关 和骨丢失通过1)定义特定的表观遗传机制，导致随着年龄和年龄的增长而导致骨骼和肌肉的丢失 2)确定可以减少或逆转这些与年龄有关的变化的具体营养干预措施。这是一个 高度集成的建议书来自一个在互动、工作效率和 合作。四个单独的项目，重点是表观遗传调控和营养相关的刺激，包括 这个应用程序。该提案还包括三个核心设施，这些设施将为 项目：包括生物统计学和生物信息学的行政核心(核心A)；骨生物学核心 (核心B)，将提供所有研究人员使用的骨骼特定技术；以及骨干细胞 核心(核心C)将向所有研究人员提供骨源性细胞，包括小鼠和人骨 骨髓祖细胞。该项目有三个具体目标：目标1将检验与年龄相关的假设 表观遗传信号的变化改变了肌肉骨骼干细胞的功能；目标2将检验这一假设 具体的饮食干预措施(例如，选择性氨基酸补充或间歇性禁食/蛋白质喂养) 可以逆转表观遗传修饰中与年龄相关的变化，并促进正常的干细胞功能；Aim 3将 测试在我们的小鼠模型中发现的与年龄相关的表观遗传修饰是 可翻译成正常的人类生理学。这个项目的长期影响将是对 随着年龄增长导致骨骼和肌肉丧失的表观遗传机制，以及减少或减少 逆转肌肉骨骼老化。