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.

促进老龄小鼠骨骼再生的实验研究 摘要 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。 截肢小鼠模型。虽然数字再生模型在最近几年获得了相当大的吸引力 多年来，并产生了大量关于再生的潜在机制的知识，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 在这个模型中，再生失败的方式类似于老年时受损的骨转换，包括 加剧骨降解活动和减弱成功植入再生骨的能力 回应。这种与年龄相关的反应类似于我们增加氧分压时看到的反应， 破坏再生指端的自然氧气微环境，这需要在 低氧和常氧氧环境都能成功再生。虽然很明显，氧气 手指的微环境是动态的，是成功再生的关键，目前尚不清楚氧气是如何 提示再生过程，以及这是否直接与细胞新陈代谢或 代谢转换，如在某些癌症中所见。这个项目中概述的研究将探索 通过专门研究氧的作用来研究衰老过程中再生失败的机制 信号和细胞新陈代谢。我们将检验再生在衰老过程中失败这一假设 关键细胞群不能成功执行代谢转换的结果 线粒体呼吸和糖酵解活性以及对氧变化的反应 微环境。为了验证这一假设，我们将评估两种年老的近交系小鼠的再生能力(目标1)。 并在转基因小鼠的衰老与代谢综合征模型(目标2)中，测试这两种基因的能力 提高小鼠品系对氧气水平变化的反应能力(目标3)。这个项目将提供有价值的 更新和老化领域的数据，并将产生有助于指导未来的新的机械性见解 治疗性干预。