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.

促进老年小鼠骨骼再生的实验研究 总结 在这项研究中，我们将探讨老年人骨和软组织再生失败的机制 趾切断小鼠模型。虽然数字再生模型最近获得了相当大的牵引力， 多年来，并导致了大量的知识，有关机制的基础再生，这 是第一个使用这个模型来探索衰老背景下的再生的研究。我们证明了 在这种模型中，再生失败的方式与老年骨转换受损相似，包括 骨降解活性加剧，成功再生骨的能力减弱 反应这种与年龄相关的反应与我们增加氧分压时看到的反应相似， 破坏再生指中的天然氧微环境，这需要在再生指之间的振荡。 低氧和常氧环境以成功再生。虽然很明显氧气 手指的微环境是动态的，对成功再生至关重要，目前还不知道氧气如何影响手指的再生。 提示再生过程，以及这是否与细胞代谢的变化直接相关， 代谢转换，如在某些癌症中所见。本项目中概述的研究将探讨 通过专门研究氧的作用， 信号和细胞代谢。我们将测试这一假设，即再生失败，在老化作为一个直接的 关键细胞群不能成功地执行代谢转换的结果 线粒体呼吸和糖酵解活性，并响应氧的变化， 微环境。为了验证这一假设，我们将评估两个老龄远系小鼠的再生（目的1） 并在衰老代谢综合征（Aim 2）转基因小鼠模型中进行了实验，并检测了这两种方法的能力 小鼠品系对氧水平变化的有效反应（目标3）。该项目将提供宝贵的 再生和老化领域的数据，并将产生新的机制见解，这将有助于指导未来 治疗干预