Soluble Motogens and Chemoattractants from Damaged Muscle

受损肌肉中的可溶性促动力剂和化学引诱剂

• 批准号: 8383029
• 负责人: Dawn D Cornelison
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383029
• 关键词: Acute; Address; Adult; Affinity; Algorithms; Area; Basic Science; Biological Assay; CXCL12 gene; Cell Therapy; Cells; Cellular biology; Charge; Chemotactic Factors; Chemotaxis; Clinical; Collaborations; Commit; Complex; Cues; Data; Data Set; Development; Disease; Distal; Duchenne muscular dystrophy; Endogenous Factors; Engraftment; Environment; Failure; Gel Chromatography; Goals; Heparin; Hepatocyte Growth Factor; Home environment; Homing; Human; In Vitro; Injection of therapeutic agent; Injury; Investigation; Ion-Exchange Chromatography Procedure; Literature; Locomotion; Maintenance; Measures; Mediating; Mediator of activation protein; Messenger RNA; Methods; Movement; Muscle; Muscle Cells; Muscle Fibers; Muscle satellite cell; Muscular Dystrophies; Myoblasts; Myopathy; Natural regeneration; Nature; Physiological; Play; Population; Positioning Attribute; Posture; Procedures; Process; Proliferating; Proteins; Proteomics; Protocols documentation; Publishing; Quality of life; Recruitment Activity; Regulation; Research Personnel; Respiration; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Software Tools; Speed; Stem Cell Development; Stem cells; Stromal Cell-Derived Factor 1; Surveys; System; Techniques; Testing; Therapeutic; Time; Tissues; Work; adult stem cell; cell motility; cell type; chemokine; human disease; improved; in vivo; injured; insight; interest; liquid chromatography mass spectroscopy; meetings; muscle hypertrophy; muscle regeneration; myogenesis; receptor; regenerative; release factor; repaired; research study; satellite cell; success; therapeutic effectiveness; working group

DESCRIPTION (provided by applicant): Skeletal muscle provides the contractile force necessary for not only locomotion but also maintenance of posture and respiration. Diseases that weaken or damage skeletal muscle therefore decrease not only quality of life but are, in cases such as Duchenne's muscular dystrophy, fatal. Differentiated muscle cells are terminally postmitotic and cannot generate new myonuclei to replace those lost to damage or disease; a population of adult stem cells termed satellite cells serves to supply new committed muscle cells for muscle hypertrophy, repair, and regeneration. Satellite cells are distributed throughout the muscle and it is well- established that if they are within an area of muscle that is damaged they will activate from their usual quiescent state and proliferate to form a pool of replacement myoblasts, which will differentiate into new muscle fibers or fuse with damaged ones to rapidly and effectively repair the muscle damage. An area of increasing interest is the potential for satellite cells distal to an area of damage to be recruited and relocated through cell migration; this would enhance the efficiency of satellite cell-mediated muscle regeneration. Therapeutic engraftments studies in which satellite cells are injected into dystrophic muscle have met with little success, and one reason has been a failure of injected cells to spread and efficiently engraft. The experiments we propose will explore the ability of factors released by damaged muscle either to promote general motility of satellite cells or to stimulate homing of satellite cels to a specific area; these studies are necessary to define the number and nature of the factors that would require further in-depth study in a later proposal. An understanding of the capacity of satellite cells to move and relocate in vivo, and the role those two activities play in muscle regeneration, would therefore add not only to basic understanding of muscle regeneration but also impact clinical therapies for DMD and other muscle diseases. In the course of these experiments, we are also working towards improved methods for automated tracking of cells in culture, in collaboration with Dr. Kanappan Palaniappan. We will produce an extremely large dataset of tracked cells, which is necessary to develop algorithms capable of replicating tracking choices made by a human researcher. Given the dramatic increase in both video data in multiple contexts and interest in cell motility in this and other systems, software tools that can accurately detect and track changes in position in a complex, high-background environment will be useful to many groups working in stem cells, development, and cell biology. PUBLIC HEALTH RELEVANCE: In addition to addressing an underexplored facet of basic research into the mechanisms of adult myogenesis, this project has high potential to contribute to the development of satellite cell-based therapies for diseases such as the muscular dystrophies. A critical area of concern in current adult myoblast and muscle- derived stem cell engraftment procedures is the unmet requirement for injected cells to, at least, disperse broadly from the injection site or, at best, actively home to either clinically-defined sites or sites of maximum damage. By providing insight into the specific guidance cues that control satellite cell movement and spread, this work will ideally suggest ways to modify current myoblast engraftment protocols to enhance their therapeutic effectiveness.

描述（由申请人提供）：骨骼肌不仅提供了运动所需的收缩力，而且还提供了姿势和呼吸的维持。因此，减弱或损害骨骼肌的疾病不仅会降低生活质量，而且在杜切恩（Duchenne）肌肉营养不良的情况下会降低生活质量。分化的肌肉细胞是终极的有丝分裂后的，无法产生新的肌核，以取代那些因损害或疾病而失去的肌核。称为卫星细胞的成年干细胞群可以为肌肉肥大，修复和再生提供新的肌肉细胞。卫星细胞分布在整个肌肉中，并且可以很好地确定，如果它们在受损的肌肉区域内，它们将从通常的静止状态中激活并扩散以形成替代的肌细胞池，从而将其分化为新的肌肉纤维或与受损的肌肉融合，以快速有效地修复肌肉损伤。越来越感兴趣的区域是卫星细胞远端通过细胞迁移招募和重新定位的损害区域的潜力。这将提高卫星细胞介导的肌肉再生的效率。将卫星细胞注入营养不良的肌肉的治疗植入研究几乎没有成功，一个原因是注射细胞无法扩散并有效地植入。我们提出的实验将探索受损肌肉释放的因素的能力，以促进卫星细胞的一般运动或刺激将卫星凝胶托入特定区域的能力。这些研究对于定义需要进一步深入研究的因素的数量和性质是必要的。因此，了解卫星细胞在体内移动和搬迁的能力以及这两种活动在肌肉再生中的作用不仅会增加对肌肉再生的基本理解，而且还会影响DMD和其他肌肉疾病的临床疗法。 在这些实验的过程中，我们还致力于改进与Kanappan Palaniappan博士合作的培养细胞自动跟踪的方法。我们将生成一个非常大的跟踪细胞数据集，这对于开发能够复制人类研究人员做出的跟踪选择的算法是必不可少的。鉴于视频数据在多个上下文中都显着增加，并且在此系统和其他系统中对细胞运动的兴趣，可以准确检测和跟踪复杂，高回复环境中的位置的软件工具对许多在干细胞，开发和细胞生物学中工作的组都会有用。 公共卫生相关性：除了针对成人肌发生机制的基础研究的一个不充分的基础研究方面外，该项目还具有很高的潜力，可以为诸如肌肉营养不良等疾病的卫星基于卫星细胞的疗法做出贡献。目前成年成年肌细胞和肌肉衍生的干细胞植入程序的关键领域是注射细胞至少从注射部位广泛分散的细胞的要求，或者最好是在临床定义的最大损害或最大损害的地方积极主动地分散。通过洞悉控制卫星细胞运动和扩散的特定指导线索，这项工作理想地将提出修改当前的成肌植入方案以增强其治疗效果的方法。