Identifying new targets to sustain skeletal muscle function

项目总结 骨骼肌萎缩是一种肌肉质量的丧失和相应的功能丧失，发生在 不同的刺激，包括停用/静止、糖皮质激素治疗、癌症、衰老和去神经。 失神经是创伤、神经肌肉疾病和年龄导致肌肉萎缩的重要因素。 人类相关的石棺减少症。肌肉卫星细胞具有独特的增殖和 在肌肉损伤的环境中再生，最近的研究表明某种程度的结构性整合 甚至是健康的、未受损伤的肌纤维，这也表明它在肌肉维护中也起到了作用。这项研究旨在 (A)查明在急性和慢性失神经期间造成肌肉萎缩的其他机制，(B)查明 肌肉卫星细胞在萎缩过程中发生的功能和基因组变化，以及(C)分配功能 新的卫星细胞富含基因的作用，期望识别新的靶点以最小化 萎缩性改变和/或维持或增强肌肉卫星细胞的增殖和再生能力。 为了实现这些目标，我们将对骨骼中发生的转录变化进行纵向分析 肌肉和骨骼肌卫星细胞在失神经萎缩期间。 这项工作与NIH及其几个机构的使命密切一致，特别是为了了解 神经系统和肌肉骨骼疾病的原因，并通过 新疗法的确定和开发。 申请者自己的长期职业目标是建立一个从事与人类相关的研究的职业 疾病，重点是确定改善诊断和治疗的翻译机会，而 为受影响的人提供专心和体恤的临床护理。继续开展本报告中提出的工作 应用程序将使他了解更多关于骨骼肌和卫星细胞生物学的知识，并开发工具 使用当代测序和信息学工具来确定参与萎缩和 再生。这些方法可以在未来的工作中应用于许多场合，如研究和临床 医学越来越受到基因组学和对复杂数据合成的依赖。每天到- 这个项目的日间数据分析要求将通过统计方面的纵向课程来补充 临床实验的分析和设计，测序平台的实践经验，机会 在信息学和肌肉发生学领域与其他人一起工作和培训，并有机会分享研究结果 在各种会议上。这些技能将大大拓宽申请者的问题范围。 能够解决现在和未来的问题，并将加强他使用大型、无偏见的数据集的能力 识别疾病发病机制中的新变化，着眼于新的临床干预措施。

PROJECT SUMMARY Skeletal muscle atrophy is a loss of muscle mass and corresponding loss of function that occurs in response to diverse stimuli including disuse/immobility, glucocorticoid treatment, cancer, aging, and denervation. Denervation is a significant contributor to muscle atrophy in trauma, neuromuscular diseases, and age- associated sarcopenia in humans. Muscle satellite cells possess the unique capacity to proliferate and regenerate in settings of muscle injury, and recent studies indicate some degree of constitutive incorporation even into healthy, uninjured myofibers, suggesting a role in muscle maintenance as well. This study aims to (a) identify additional mechanisms causing muscle atrophy during acute and chronic denervation, (b) identify functional and genomic changes that occur in muscle satellite cells during atrophy, and (c) assign functional roles for novel satellite cell-enriched genes, with the expectation of identifying novel targets for minimizing atrophic changes and/or sustaining or enhancing muscle satellite cell proliferative and regenerative capacity. To achieve these goals, we will conduct a longitudinal analysis of transcriptional changes occurring in skeletal muscle and in skeletal muscle satellite cells during denervation atrophy. This work aligns closely with the mission of the NIH and several of its agencies, specifically to understand the causes of neurologic and musculoskeletal disease, and to reduce the burden of these conditions through the identification and development of new therapies. The applicant’s own long-term professional goal is to establish a career conducting research related to human disease with an emphasis on identifying translational opportunities to improve diagnosis and treatment, while providing dedicated and compassionate clinical care for those affected. Pursuing the work proposed in this application will allow him to learn more about skeletal muscle and satellite cell biology, and to develop facility using contemporary sequencing and informatics tools to identify pathways involved in atrophy and regeneration. These methods can be applied in numerous contexts in future work, as research and clinical medicine become increasingly influenced by genomics and reliance on synthesis of complex data. The day-to- day data analysis requirements of this project will be complemented by longitudinal coursework in statistical analysis and design of clinical experiments, practical experience with sequencing platforms, opportunities to work and train with others in the fields of both informatics and myogenesis, and opportunities to share findings at conferences and meetings. These skills will significantly broaden the scope of questions the applicant will be able to address now and in the future, and will strengthen his ability to use large, unbiased data sets to identify novel changes during disease pathogenesis with an eye toward new clinical interventions.