Promoting Skeletal Regeneration in Aged Mice

促进老年小鼠骨骼再生

• 批准号: 9353034
• 负责人: Mimi C Sammarco
• 金额: $ 24.32万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9353034
• 关键词: Affect; Age; Aging; Amputation; Attenuated; Bone Regeneration; Bone Tissue; Caring; Cells; Cellular Metabolic Process; Cellular Structures; Cues; Data; Deposition; Digit structure; Elderly; Energy Metabolism; Environment; Event; Exhibits; Fracture Healing; Future; Homeostasis; Hypoxia; Knockout Mice; Knowledge; Light; Link; Malignant Neoplasms; Mentors; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Mouse Strains; Mus; Natural regeneration; Osteoblasts; Osteogenesis; Osteoporosis; Oxidative Phosphorylation; Oxygen; Pathway interactions; Pattern; Phase; Population; Process; Proliferating; Quality of life; Regenerative Medicine; Research; Respiration; Role; Signal Transduction; Stem cells; Structure; System; Tendon structure; Testing; Therapeutic Intervention; Tissues; Traction; Transgenic Mice; Undifferentiated; Wound Healing; aerobic glycolysis; age related; aged; blastema; bone; bone aging; bone healing; bone loss; bone quality; bone turnover; cost; digit regeneration; healing; insight; metabolic profile; mouse model; older patient; regenerative; response; skeletal regeneration; soft tissue; tissue regeneration; wound closure

Promoting Skeletal Regeneration in Aged Mice Summary In this study we will investigate the mechanisms behind failed bone and soft tissue regeneration in the aged digit amputation mouse model. While the digit regeneration model has gained considerable traction in recent years and resulted in a substantial amount of knowledge regarding mechanisms underlying regeneration, this is the first study that will use this model to explore regeneration the context of aging. We show that regeneration fails in this model in ways that are similar to compromised bone turnover in old age, including exacerbated bone degradation activity and the attenuated ability to mount a successful regenerative bone response. This age-related response is similar to the one seen when we applying increased oxygen tension, disrupting the native oxygen microenvironment in the regenerating digit, which requires an oscillation between both hypoxic and normoxic oxygen environments for successful regeneration. While it is clear that the oxygen microenvironment of the digit is dynamic and critical to successful regeneration, it is not known how oxygen cues the regenerative process and whether or not this is directly linked to changes in cell metabolism or metabolic switching, as is seen in certain cancers. The studies outlined in this project will explore the mechanisms through which regeneration fails during aging by specifically investigating the role of oxygen signals and cellular metabolism. We will test the hypothesis that regeneration fails in aging as a direct result of the inability of key cell populations to successfully execute metabolic switching between mitochondrial respiration and glycolytic activity and to respond to changes in the oxygen microenvironment. To test this hypothesis we will evaluate regeneration in both aged outbred mice (Aim 1) and in a transgenic mouse model of aging with metabolic syndrome (Aim 2), and test the ability of these two strains of mice to respond effectively to changes in oxygen levels (Aim 3). This project will provide valuable data in both the regeneration and aging fields and will yield new mechanistic insights that will help guide future therapeutic intervention.

促进老年小鼠的骨骼再生 概括 在这项研究中，我们将研究老年人的骨骼和软组织再生的机制 数字截肢鼠标模型。虽然数字再生模型在最近获得了相当大的吸引力 多年，并导致了有关再生基本机制的大量知识， 是第一个将使用该模型探索再生衰老的研究。我们表明 这种模型的再生以类似于老年骨转换的方式失败，包括 恶化的骨降解活性和衰减的成功再生骨的能力 回复。这种与年龄相关的反应类似于当我们应用氧气张力增加时看到的反应， 破坏重生数字中的天然氧微环境，这需要在 成功再生的低氧和常氧氧气环境。虽然很明显氧气 数字的微环境是动态的，对成功再生至关重要，尚不清楚氧气如何 提示再生过程以及这是否与细胞代谢的变化直接相关或 代谢切换，如某些癌症所示。该项目中概述的研究将探索 通过专门研究氧的作用，再生在衰老过程中通过的机制失败 信号和细胞代谢。我们将检验以下假设，即再生在衰老中失败 关键细胞种群无法成功执行代谢切换的结果 线粒体呼吸和糖酵解活性，并应对氧气的变化 微环境。为了检验这一假设，我们将评估两只老年杂种小鼠的再生（AIM 1） 在与代谢综合征衰老的转基因小鼠模型中（AIM 2），并测试这两个的能力 小鼠菌株有效地应对氧气水平的变化（AIM 3）。该项目将提供有价值的 再生和老化领域的数据，并将产生新的机械见解，以帮助指导未来 治疗干预。