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）：骨骼肌不仅提供运动所需的收缩力，还提供维持姿势和呼吸所需的收缩力。因此，削弱或损害骨骼肌的疾病不仅会降低生活质量，而且在杜氏肌营养不良症等病例中是致命的。分化的肌细胞在有丝分裂末期不能产生新的肌核来取代那些因损伤或疾病而丢失的肌核;称为卫星细胞的成体干细胞群体用于为肌肉肥大、修复和再生提供新的定向肌细胞。卫星细胞分布在整个肌肉中，并且公认的是，如果它们位于受损的肌肉区域内，它们将从其通常的静止状态激活并增殖以形成替代成肌细胞池，其将分化成新的肌纤维或与受损的肌纤维融合以快速有效地修复肌肉损伤。一个越来越受关注的领域是通过细胞迁移招募和重新定位损伤区域远端的卫星细胞的潜力;这将提高卫星细胞介导的肌肉再生的效率。将卫星细胞注射到营养不良的肌肉中的治疗性移植研究几乎没有成功，一个原因是注射的细胞无法扩散和有效移植。我们提出的实验将探索受损肌肉释放的因子促进卫星细胞的一般运动性或刺激卫星细胞归巢到特定区域的能力;这些研究对于确定因子的数量和性质是必要的，这些因子需要在以后的提案中进一步深入研究。因此，了解卫星细胞在体内移动和重新定位的能力，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，而且会影响DMD和其他肌肉疾病的临床治疗。 在这些实验的过程中，我们还与Kanappan Palaniappan博士合作，致力于改进自动跟踪培养细胞的方法。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所做跟踪选择的算法是必要的。鉴于在多种背景下视频数据的急剧增加以及对该系统和其他系统中细胞运动的兴趣，可以准确检测和跟踪复杂高背景环境中位置变化的软件工具将对干细胞，发育和细胞生物学的许多小组有用。 公共卫生相关性：除了解决成人肌生成机制基础研究的一个未充分探索的方面外，该项目还具有很大的潜力，有助于开发基于卫星细胞的疾病治疗方法，如肌营养不良症。在目前的成人成肌细胞和肌肉来源的干细胞移植程序中，一个关键的关注领域是未满足的要求，即注射的细胞至少从注射部位广泛分散，或者最好主动归巢到临床定义的部位或最大损伤的部位。通过提供对控制卫星细胞运动和扩散的特定指导线索的深入了解，这项工作将理想地提出修改当前成肌细胞植入方案以提高其治疗效果的方法。