Satellite cell activation and its paracrine impact on fiber phenotype

卫星细胞激活及其旁分泌对纤维表型的影响

• 批准号: RGPIN-2014-05770
• 负责人: Anderson, Judy
• 金额: $ 2.99万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=567376
• 关键词: Satellite; cell; activation; its; paracrine

My research aims to discover novel, practical mechanisms that can be used to improve human and animal health. Knowledge of the biology of muscle satellite cells, the stem cells in skeletal muscle, and their interactions with muscle fibers and surrounding tissues during development, disease and regeneration is largely based on studies of mammalian mouse muscle. In the past grant cycle I initiated a comparative approach to the processes regulating satellite cell behaviour and activation. Activation of satellite cells into the cell cycle for proliferation is the essential first step in muscle growth and regeneration, and we are one of a few labs studying activation explicitly. We recently focused on zebrafish muscle, since such knowledge could have potent application to the aquaculture industry in boosting fish-meat production. For the proposed work, we aim to understanding the interplay of satellite cell activity with muscle development, function and regeneration in order to advance Canadian innovation capacity in promoting muscle growth in animals and muscle health in humans. My program trained 28 HQP during the past NSERC grant cycle, specifically in developing a new approach to comparative satellite cell biology. Together with trainees, I brought our previous discoveries on chemical, mechanical and protein signals regulating satellite cell behaviour to studies of fish-muscle growth, a research area critical to feeding our rising global populations and yet lacking in such fundamental information at the cellular level. The outcomes of activation are essential knowledge for designing new drug and rehabilitation therapies for human health. My discoveries that activation is instigated by nitric oxide (Anderson 2000) and that a stretch liberates that gas (Wozniak and Anderson 2007, 2009) are the scientific bases of drug discovery, my 3 patents, and even a clinical trial on Duchenne dystrophy by other investigators. Two objectives of my proposed research address a major gap in our understanding of the impact of ectothermy in teleosts on processes regulating muscle growth. We will study the regulation of satellite cells in specific fish species and during development, including the ancient sturgeon and parasitic and free-living lampreys and compare them to our recent findings on zebrafish muscle. These select animals represent species with evolutionary modifications in life-history and particular adaptations affecting muscle growth, and are important in Manitoba and Canada. Departmental expertise and animal resources will also be potent assets in proposed HQP training. The exciting discovery with international collaborators, that activated satellite cells make the axon-guidance protein, Semaphorin3A, will be used in objective 3 to study the impact of Sema3A on functional muscle regeneration. The idea that satellite cells actively direct regeneration is novel and unique in the literature - its significance stems from the importance of activation pathways that determine how satellite cells contribute to and shape the capacity for muscle growth and repair. Its novelty is that study of signals to AND from satellite cells and muscle fibers will give insights about how those signals optimize growth and regeneration. My lab is unique in using isolated fibers to study satellite cell activation at the cellular level and across species. Cell-level studies are essential to learning how satellite cells regulate muscle responsiveness and phenotype as the satellite-cell population is heterogeneous, even on a single fiber. This proposed work has potential applications to increase industrial meat production by aquaculture and promote muscle regeneration, growth and rehabilitation after injury, atrophy and disease conditions.

我的研究旨在发现可用于改善人类和动物健康的新颖、实用的机制。关于肌肉卫星细胞、骨骼肌干细胞的生物学知识，以及它们在发育、疾病和再生过程中与肌纤维和周围组织相互作用的知识很大程度上基于对哺乳动物小鼠肌肉的研究。在过去的资助周期中，我发起了一种调节卫星细胞行为和激活过程的比较方法。激活卫星细胞进入细胞周期进行增殖是肌肉生长和再生的重要第一步，我们是少数几个明确研究激活的实验室之一。我们最近关注斑马鱼肌肉，因为这些知识可以有效应用于水产养殖业，提高鱼肉产量。对于拟议的工作，我们的目标是了解卫星细胞活动与肌肉发育、功能和再生的相互作用，以提高加拿大在促进动物肌肉生长和人类肌肉健康方面的创新能力。我的项目在过去的 NSERC 拨款周期中培训了 28 名 HQP，特别是开发比较卫星细胞生物学的新方法。我与学员一起，将我们之前在调节卫星细胞行为的化学、机械和蛋白质信号方面的发现带到了鱼类肌肉生长的研究中，这是一个对于养活不断增长的全球人口至关重要的研究领域，但在细胞水平上缺乏此类基本信息。 激活的结果是为人类健康设计新药和康复疗法的重要知识。我发现一氧化氮会引发激活（Anderson 2000），而拉伸会释放这种气体（Wozniak 和 Anderson 2007、2009），这些发现是药物发现的科学基础、我的 3 项专利，甚至是其他研究人员对杜氏营养不良症的临床试验。 我提出的研究的两个目标解决了我们对硬骨鱼变温对肌肉生长调节过程影响的理解上的一个重大差距。我们将研究特定鱼类和发育过程中卫星细胞的调节，包括古代鲟鱼、寄生和自由生活的七鳃鳗，并将它们与我们最近对斑马鱼肌肉的发现进行比较。这些精选动物代表了生活史中具有进化改变和影响肌肉生长的特殊适应的物种，在马尼托巴省和加拿大很重要。部门专业知识和动物资源也将成为拟议的总部培训中的重要资产。 与国际合作者合作的令人兴奋的发现，即激活的卫星细胞产生轴突引导蛋白 Semaphorin3A，将用于目标 3，以研究 Sema3A 对功能性肌肉再生的影响。卫星细胞主动指导再生的想法在文献中是新颖且独特的——其重要性源于激活途径的重要性，激活途径决定卫星细胞如何促进和塑造肌肉生长和修复的能力。其新颖之处在于，对来自卫星细胞和肌肉纤维的 AND 信号的研究将深入了解这些信号如何优化生长和再生。我的实验室在使用分离纤维来研究细胞水平和跨物种的卫星细胞激活方面是独一无二的。细胞水平研究对于了解卫星细胞如何调节肌肉反应性和表型至关重要，因为卫星细胞群是异质的，即使在单根纤维上也是如此。这项拟议的工作具有潜在的应用价值，可以增加水产养殖的工业肉类产量，并促进受伤、萎缩和疾病后的肌肉再生、生长和康复。