Identifying new targets to sustain skeletal muscle function

项目摘要 骨骼肌萎缩是一种肌肉质量的损失和相应的功能损失， 多种刺激，包括废用/不动、糖皮质激素治疗、癌症、衰老和去神经支配。 去神经支配是创伤、神经肌肉疾病和年龄引起的肌肉萎缩的重要原因。 相关的肌肉减少症。肌肉卫星细胞具有独特的增殖能力， 在肌肉损伤的情况下再生，最近的研究表明一定程度的组成性掺入 甚至进入健康的、未受伤的肌纤维，这表明它在肌肉维护中也有作用。本研究旨在 (a)鉴定在急性和慢性去神经支配期间引起肌肉萎缩的另外的机制，（B）鉴定 在萎缩期间在肌肉卫星细胞中发生的功能和基因组变化，以及（c）分配功能性 新的卫星细胞富集基因的作用，期望确定新的目标，以减少 萎缩性变化和/或维持或增强肌肉卫星细胞增殖和再生能力。 为了实现这些目标，我们将对骨骼肌中发生的转录变化进行纵向分析， 肌和骨骼肌卫星细胞在失神经萎缩。 这项工作与NIH及其几个机构的使命密切相关，特别是为了了解 神经和肌肉骨骼疾病的原因，并通过 识别和开发新疗法。 申请人自己的长期职业目标是建立一个从事与人类有关的研究的职业， 疾病，重点是确定转化的机会，以改善诊断和治疗，而 为受影响的人提供专门和富有同情心的临床护理。为开展本报告中提出的工作， 申请将使他能够更多地了解骨骼肌和卫星细胞生物学，并开发设施， 使用当代测序和信息学工具来确定参与萎缩的途径， 再生这些方法可以在未来的工作中应用于许多情况下，如研究和临床 医学越来越受到基因组学和对复杂数据综合的依赖的影响。日- 该项目的日常数据分析要求将通过统计学纵向课程来补充 临床实验的分析和设计，测序平台的实践经验， 在信息学和肌生成领域与他人一起工作和培训，并有机会分享发现 在各种会议上。这些技能将大大拓宽问题的范围，申请人将 能够解决现在和未来的问题，并将加强他使用大型无偏见数据集的能力， 确定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.