The role of cMET in satellite cells during muscle regeneration

cMET 在肌肉再生过程中卫星细胞中的作用

基本信息

批准号：
8594554
负责人：
Micah Taube Webster
金额：
$ 5.22万
依托单位：
CARNEGIE INSTITUTION OF WASHINGTON, D.C.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8594554
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Acute Address Adult Affect Alleles Alveolar Behavior Binding Biology Cell Culture Techniques Cell Proliferation Cell Survival Cell physiology Cells Child Complement Cultured Cells Data Defect Development Direct Lytic Factors Docking Embryonal Rhabdomyosarcoma Embryonic Development Genes Goals Harvest Hepatocyte Growth Factor Immigration In Vitro Injury Ligands Liver Regeneration Malignant Neoplasms Mediating Methods Modeling Molecular Monitor Mus Muscle Muscle Fibers Muscle satellite cell Muscular Dystrophies Myoblasts Natural regeneration Needles Nude Mice Operative Surgical Procedures Phenotype Play Proliferating Proto-Oncogenes Radiation Receptor Protein-Tyrosine Kinases Relative (related person)Research Rhabdomyosarcoma Role Signal Pathway Signal Transduction Site Skeletal Muscle Stem cells Tamoxifen Testing Time Transplantation Treatment Protocols Variant Work adult stem cell anticancer research base cell behavior cell motility cell type chemotherapy clinical phenotype clinically relevant growth factor receptor-bound protein 2 in vivo meetings migration muscle regeneration mutant precursor cell progenitor public health relevance recombinase repaired response response to injury sarcoma satellite cell skin regeneration soft tissue src-Family Kinases stem cell biology therapy development tissue regeneration translational study tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma that occurs in children. Current treatment protocols for RMS combine surgery, chemotherapy, and radiation, yet fail to cure 30% of RMS cases. Though heterogeneous in clinical phenotype, all RMS are thought to arise from skeletal muscle precursor cells. The proto-oncogene, c-Met, is deregulated in at least two types of RMS, embryonal and the more aggressive alveolar, and has been identified as a potential target for treating RMS. c-Met encodes a receptor tyrosine kinase. Activation by its ligand, Hepatocyte Growth Factor (HGF), triggers multiple signaling cascades that modulate cell survival, proliferation, and migration of various cultured cell types. In vivo, the HGF/c-MET axis mediates efficient adult liver and skin regeneration in response to injury. Furthermore, this axis is indispensible for the migration and proliferation of appendicular muscle progenitors during embryogenesis. Based on these findings, c-Met likely plays a role in adult muscle stem cells, i.e. satellite cells (SCs), during injury induced skeletal muscle regeneration. In uninjured muscle, quiescent SCs express c-Met. Upon muscle injury, SCs activate to proliferate and become myoblasts (muscle precursor cells) that accumulate at sites of injury where they fuse to form new muscle fibers. c-Met and Hgf are up-regulated in the muscle during this period, suggesting an involvement of these genes in myoregeneration. Preliminary data show that conditionally inactivated c-Met in adult mouse SCs disrupts injury induced muscle regeneration. Consistent with a role for c-MET in SC migration, c-Met mutant SCs do not accumulate at a defined muscle injury site. These preliminary data indicate that c-MET signaling enables SC migration and potentially other aspects of the SC response to muscle injury. Aim 1) Because c-MET elicits multiple signaling cascades, the parameters of the c-Met mutant SC phenotype will be defined. Aim 2) The extent of normal SC migration and the role that c- MET and HGF play in directing SCs to an injury site will be determined. Aim 3) Branches of c-MET signaling important for SC migration and proliferation will be identified and further tested for ability to enhance SC migration and muscle regeneration. Finally, clonal analysis will be used to assess the functional significance of specific branches of c-MET signaling in SCs, potentially leading to a new model of c-MET induced tumorigenesis. The relative contributions of local SC proliferation versus recruitment of migratory SCs to muscle regeneration have long been debated. Moreover, the molecular signals that guide SC to injury sites has not been resolved. Studying the HGF/c-MET axis in SCs will inform these clinically relevant issues. Identifying c-MET effectors in adult muscle precursors is crucial not only for understanding muscle stem cell biology, but also for understanding general principles of stem cell mediated regeneration, and for developing therapies for RMS that exploit c-MET signaling pathways. As deregulation of c-MET signaling is implicated in myriad tumors, this research may be relevant to multiple cancers.

描述（由申请人提供）：横纹肌肉瘤（RMS）是儿童中最常见的软组织肉瘤。 RMS的当前治疗方案结合了手术，化学疗法和放射线，但无法治愈30％的RMS病例。尽管在临床表型中异质，但所有RMS都被认为是骨骼肌前体细胞引起的。原始癌基因C-MET在至少两种类型的RMS，胚胎和更具侵略性的肺泡中进行了管制，并已被鉴定为治疗RMS的潜在靶标。 C-MET编码受体酪氨酸激酶。通过其配体，肝细胞生长因子（HGF）激活，触发了多种信号级联，可调节各种培养细胞类型的细胞存活，增殖和迁移。在体内，HGF/C-MET轴响应损伤介导有效的成年肝脏和皮肤再生。此外，该轴对于胚胎发生过程中阑尾肌肉祖细胞的迁移和增殖是必不可少的。根据这些发现，C-MET可能在损伤引起的骨骼肌再生过程中在成年肌肉干细胞（即卫星细胞（SC）中起作用。在未受伤的肌肉中，静态的SC表示C-MET。肌肉损伤后，SC会激活以增殖并成为肌细胞（肌肉前体细胞），该成肌细胞积聚在损伤部位，它们融合形成新的肌肉纤维。在此期间，C-MET和HGF在肌肉中被上调，这表明这些基因参与了肌关系。初步数据表明，成年小鼠SC中有条件灭活的C-MET破坏了损伤引起的肌肉再生。与C-MET在SC迁移中的作用一致，C-Met突变体SC不会在定义的肌肉损伤部位积累。这些初步数据表明，C-MET信号传导可实现SC迁移以及SC对肌肉损伤反应的其他方面。目标1）由于C-MET会引起多个信号级联，因此将定义C-Met突变体SC表型的参数。目标2）将确定正常SC迁移的程度以及C-MET和HGF在将SC引导到伤害部位中的作用。目标3）C-MET信号的分支对于SC迁移和增殖很重要，并进一步测试了增强SC迁移和肌肉再生的能力。最后，克隆分析将用于评估特定分支的功能意义 SC中的C-MET信号传导可能导致新的C-Met诱导肿瘤发生模型。局部SC的扩散与募集迁移SC对肌肉再生的相对贡献一直在争论。此外，尚未解决将SC引导为损伤部位的分子信号。在SCS中研究HGF/C-MET轴将为这些临床上有关的问题提供信息。在成年肌肉前体中识别C-MET效应子不仅对于理解肌肉干细胞生物学至关重要，而且对于理解干细胞介导的再生的一般原理以及开发利用C-MET信号通路的RMS的疗法。由于C-MET信号的放松管制与无数肿瘤有关，因此这项研究可能与多种癌症有关。