Age Induced Impairment of Nutrient Signaling Results in Bone Loss

这是我们目前资助的计划项目（P01）奖的竞争性续期申请，题为“年龄- 诱导的营养信号传导损伤导致骨丢失”。骨质疏松症是一个主要的公共卫生问题 影响了四千四百万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，并迅速上升。一个关键的障碍，以纠正问题的脆弱性和骨质疏松症是穷人 了解营养相关的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控系统（例如，miRNA，乙酰化）， 通过营养信号通路作用于干细胞，影响肌肉骨骼功能。该项目将 提高科学知识，技术能力和临床实践，因为它们与年龄引起的肌肉有关 和骨丢失，通过1）定义特定的表观遗传机制，导致骨和肌肉随着年龄的增长而丢失， 2)确定具体的营养干预措施，可以减少或扭转这些与年龄有关的变化。这是一 一个高度整合的提案，来自一个具有既定互动记录、生产力和 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，将为 项目：管理核心（核心A），包括生物统计学和生物信息学;骨生物学核心 (Core B），将提供所有研究者使用的骨特异性技术;以及骨干细胞 核心（核心C），将为所有研究者提供骨源性细胞，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将检验与年龄有关的假设， 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（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，促进正常干细胞功能; Aim 3将 测试假设，即在我们的小鼠模型中鉴定的相关年龄相关的表观遗传修饰是 可以转化为正常的人类生理学。该项目的长期影响将是对 骨和肌肉随年龄减少的表观遗传机制，以及减少或 逆转肌肉骨骼老化

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.