Novel Mechanisms of Extracellular Matrix Regulation During Development

发育过程中细胞外基质调节的新机制

基本信息

批准号：
9142640
负责人：
Clarissa A Henry
金额：
$ 35.53万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9142640
关键词：
Address Adhesions Affect Biological CRISPR/Cas technology Cells Cessation of life Child Childhood Complex Data Deposition Development Disease Down-Regulation Duchenne muscular dystrophy Embryonic Development Employee Strikes Extracellular Matrix Fast-Twitch Muscle Fibers Fiber Fibroblast Growth Factor Fibronectins Fibrosis Genes Genetic Goals Health Homeostasis Injury Knowledge Laminin Locomotion MMP11 gene Matrix Metalloproteinase Inhibitor Medial Mediating Merosin Metabolic Microscopy Mission Modeling Morphogenesis Muscle Muscle Cells Muscle Development Muscle Fibers Muscle function Muscular Dystrophies Mutagenesis Mutation Myopathy Natural regeneration Organ Other Genetics Pathway interactions Patients Physiology Play Proteins Public Health Publishing Regulation Research Role Signal Pathway Signal Transduction Skeletal Muscle Slow-Twitch Muscle Fibers Structure Techniques Testing Time Tissues To specify Up-Regulation Ursidae Family Zebrafish adverse outcome base congenital muscular dystrophy effective therapy extracellular improved innovation insight muscle degeneration muscle regeneration novel paxillin polymerization premature prevent research study stromelysin 3 zebrafish development

项目摘要

The specification and morphogenesis of skeletal muscle is critical for normal embryonic development. The critical role of muscle is highlighted by the fact that congenital muscular dystrophies cause debilitating disease in children and are associated with premature death in nearly all patients affected. Many congenital muscular dystrophies, such as Duchenne, Ulrich, and Merosin-deficient muscular dystrophies, are caused by mutations in adhesion complexes that anchor muscle cells to their surrounding extracellular matrix (the myomatrix). In addition to being required for muscle development, the myomatrix plays a fundamental role in muscle homeostasis because it bears much of the passive load. Despite the critical role that the myomatrix plays in muscle development and physiology, the mechanisms underlying myomatrix development are not known. In particular, mechanisms that mediate the dynamic changes in myomatrix composition are not well understood. Fibronectin (Fn) is a myomatrix protein that is necessary for muscle development and regeneration. Fn is transiently upregulated during muscle development and regeneration. The subsequent downregulation of Fn levels is important because excess Fn deposition leads to fibrosis. Fibrosis is the aberrant deposition of extracellular matrix proteins. In the context of skeletal muscle, the replacement of contractile muscle tissue with Fn-rich fibrotic material diminishes muscle function. Therefore, Fn levels have to be tightly controlled. The mechanisms that mediate Fn polymerization during muscle development are beginning to be elucidated, but nothing is known about how Fn is downregulated. Our central hypothesis is that the myomatrix protein laminin, along with Matrix Metalloproteinase 11 (Mmp11) and Tissue Inhibitor of Matrix Metalloproteinase 2a (Timp2a), comprise a regulatory network that controls Fn levels, muscle fiber type specification, and muscle morphogenesis. This hypothesis is based on our preliminary data showing that laminin polymerization mediates Mmp11 localization and that Mmp11 is necessary and sufficient for Fn downregulation during zebrafish development. Preliminary data also suggest that Timp2a is required for Fn regulation. Understanding Fn regulation during muscle development and regeneration is significant because transient Fn is necessary; but too much or sustained Fn is deleterious. These experiments are innovative because they are the first to address mechanisms underlying Fn downregulation during development, the first to address Mmp11 function during muscle development, and the first to analyze crosstalk between laminin and Fn. The contribution of this research will be identification of novel mechanisms regulating Fn levels and roles for Fn in muscle fiber type specification. Completion of this research will significantly advance our long-term goal, which is to understand how signaling between muscle cells and their myomatrix mediates muscle development, homeostasis, and regeneration.

骨骼肌的规范和形态发生对于正常的胚胎发育至关重要。这先天性肌肉营养不良引起了使人衰弱的疾病，肌肉的关键作用得到了强调在儿童中，几乎所有受影响的患者都与过早死亡有关。许多先天性肌肉肌营养不良，例如Duchenne，Ulrich和缺乏梅罗蛋白的肌营养不良，是由突变引起的在粘附复合物中，将肌肉细胞锚定在其周围的细胞外基质（肌瘤）上。在除了肌肉发育所需的需要，肌瘤在肌肉中起着基本作用体内平衡是因为它承担了很多被动负载。尽管Myomatrix在肌肉发育和生理学，肌瘤发育的基础机制尚不清楚。在特别是介导肌瘤组合物中动态变化的机制尚不清楚。纤连蛋白（FN）是肌肉发育和再生所必需的肌瘤蛋白。 fn是在肌肉发育和再生过程中瞬时上调。随后的FN下调水平很重要，因为过量的FN沉积会导致纤维化。纤维化是异常沉积细胞外基质蛋白。在骨骼肌的背景下，用富含FN的纤维化材料会降低肌肉功能。因此，必须严格控制FN水平。这在肌肉发育过程中介导FN聚合的机制已开始阐明，但是关于FN的下调一无所知。我们的中心假设是肌瘤蛋白层粘连蛋白，以及基质金属蛋白酶11（MMP11）和基质金属蛋白酶2A（TIMP2A）的组织抑制剂，包括控制FN水平，肌肉纤维类型和肌肉的监管网络形态发生。该假设基于我们的初步数据，表明层粘连蛋白聚合介导MMP11定位，并且在斑马鱼的发展。初步数据还表明，FN调节需要TIMP2A。理解肌肉发育和再生过程中的FN调节很重要，因为瞬态FN是必要的。但是太多或持续的FN是有害的。这些实验具有创新性，因为它们是第一个解决开发过程中FN下调的基础机制，第一个解决MMP11功能在肌肉发育过程中，也是第一个分析层粘连蛋白和FN之间的串扰的。这个贡献研究将确定调节FN水平和FN在肌肉纤维类型中的作用的新机制规格。这项研究的完成将大大提高我们的长期目标，即了解肌肉细胞及其肌瘤之间的信号如何介导肌肉发育，体内平衡和再生。