The role of cellular senescence in skeletal muscle loss and dysfunction

细胞衰老在骨骼肌损失和功能障碍中的作用

• 批准号: 10737207
• 负责人: Davis A. Englund
• 金额: $ 10.49万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737207
• 关键词: Address; Adult; Age; Aging; Anatomy; Bioinformatics; Biology; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cell Nucleus; Cells; Chronology; Clinic; Complement; DNA Damage; Data; Disease; Doxycycline; Drug Targeting; Elderly; Epigenetic Process; Etiology; Fiber; Fibrosis; Foundations; Functional disorder; Funding; Gene Expression Profiling; Giant Cells; Health; Heterogeneity; Human; Image; Individual; Knowledge; Label; Measures; Mediating; Mentors; Methods; Microscopy; Mitotic; Modeling; Molecular; Mononuclear; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Personal Satisfaction; Phase; Phenotype; Physical Function; Population; Positioning Attribute; Predisposition; Prevention; Process; Property; Publishing; Quality of life; Research; Research Personnel; Research Training; Resolution; Role; Skeletal Muscle; Stimulus; Techniques; Testing; Therapeutic; Tissues; Training; Transgenic Mice; Translating; United States National Institutes of Health; Wasting Syndrome; Withdrawal; Work; age related; aged; biomarker validation; blood-based biomarker; career; cell type; clinically relevant; drug discovery; effective therapy; functional improvement; gain of function; health care service utilization; improved; in vivo; insight; loss of function; mitochondrial dysfunction; molecular imaging; mouse model; multiple omics; muscle aging; muscle form; muscle strength; new therapeutic target; novel; oncoprotein p21; overexpression; pharmacologic; postmitotic; programs; response; sarcopenia; satellite cell; senescence; single-cell RNA sequencing; skeletal muscle wasting; skills; synergism; therapeutic target; tool; transcriptome; translational research program

PROJECT SUMMARY/ABSTRACT The objectives of this proposal are to (1) obtain the experimental skills and career training necessary to develop a translational research program investigating mechanisms underlying skeletal muscle wasting and (2) generate the data necessary to determine the feasibility of targeting senescent cells to restore muscle size and function. Sarcopenia is a debilitating age-related skeletal muscle wasting syndrome associated with poor quality of life and high health care utilization. The etiology of sarcopenia is not fully understood, and there are currently no effective treatments. Identifying the processes mediating sarcopenia is critical for developing pharmacologic therapies. Senescent cells accumulate with age and at the anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Indeed, in mice, the targeted elimination of senescent cells improves function and parameters of health in multiple tissues. Our preliminary data show (1) senescent post- mitotic muscle fibers accumulate in sarcopenic mice, (2) the cyclin-dependent kinase inhibitor p21 is a critical regulator of muscle fiber senescence, and (3) a subset of myonuclei within multi-nucleated muscle fibers are uniquely vulnerable to senescence induction. I will use mouse models that allow for muscle fiber-specific labeling and modulation of p21 to advance our understanding for muscle fiber senescence and examine the direct contribution of senescence to muscle dysfunction. In Aim 1, I will overexpress p21 in muscle fibers in vivo and apply well-validated markers of senescence together with transcriptome-wide analyses to determine the core properties of muscle fiber senescence and identify regulatory processes that may serve as therapeutic targets. In Aim 2, I will use gain-of-function and loss-of-function p21 models and assess measures of muscle health, function, and size to determine the clinical relevance of senescent cell burden in skeletal muscle. In Aim 3, I will use myonuclear identification and isolation techniques together multiomic profiling to examine differences between senescent and non-senescent subsets of myonuclei to gain new insight into the factors regulating myonuclear senescence. The K99 phase will be conducted at Mayo Clinic and will focus on obtaining mentored training in methods required to complete the proposed aims. The R00 phase will be conducted in my independent lab and will focus on analyzing mouse tissues and data, publishing findings, and developing an R01 application based on these results. This proposal synergizes new skills in advanced senescent cell identification, imaging, bioinformatics, and drug target discovery techniques to create a research trajectory that is distinct from my mentors’ foci. This work will produce a robust foundation for an independent research career elucidating cellular mechanisms of skeletal muscle dysfunction with the aim of translating these findings into therapies to improve human health and well-being.

项目摘要/摘要 该提案的目标是（1）获得必要的实验技能和职业培训 制定一项翻译研究计划，研究骨骼肌浪费的基础机制，（2） 生成确定靶向感觉细胞以恢复肌肉大小和的可行性所必需的数据 功能。肌肉减少症是一种使年龄有关的骨骼肌浪费综合症 生活质量和高度医疗保健利用。肌肉减少症的病因尚不完全了解，还有 目前没有有效的治疗。确定介导肌肉减少症的过程对于开发至关重要 药理学疗法。衰老细胞随着年龄的增长和疾病解剖部位积聚。那， 它们被认为是逻辑治疗靶标。实际上，在小鼠中，靶向消除感觉细胞 改善多次健康的功能和健康参数。我们的初步数据显示（1）Senscent后 有丝分裂肌纤维积聚在肌肉减少小鼠中，（2）细胞周期蛋白依赖性激酶抑制剂P21是关键 肌肉纤维感应的调节剂，以及（3）多核肌肉纤维中的肌瘤的子集是 独特的诱导感受。我将使用允许特定肌肉纤维的鼠标模型 p21的标签和调制，以提高我们对肌肉纤维感应的理解并检查 感应对肌肉功能障碍的直接贡献。在AIM 1中，我将在肌肉纤维中过度表达P21 体内并应用良好的感应标记，以及整个转录组的分析，以确定 肌肉纤维感应的核心特性并确定可以用作治疗的调节过程 目标。在AIM 2中，我将使用功能获得和功能丧失P21模型和肌肉的评估指标 健康，功能和大小，以确定骨骼肌中感觉细胞伯嫩的临床相关性。在 AIM 3，我将使用肌核识别和隔离技术一起检查 肌核的感官和非发透镜亚集之间的差异，以获得对因素的新见解 调节肌能感受。 K99阶段将在Mayo诊所进行，并将重点放在 在完成提议的目标所需的方法中获得修补培训。 R00阶段将是 在我的独立实验室中进行，将重点介绍分析的小鼠组织和数据，发布结果以及 根据这些结果开发R01应用程序。该提议协同高级技能 感觉细胞识别，成像，生物信息学和药物目标发现技术，以创建研究 与导师的焦点不同的轨迹。这项工作将为独立 研究职业阐明了骨骼肌功能障碍的细胞机制，目的是翻译 这些发现是改善人类健康和福祉的疗法。