Regulation of Morphogenesis and Extracellular Matrix Assembly at the Myotendinous Junction

肌腱连接处形态发生和细胞外基质组装的调节

基本信息

批准号：
9217590
负责人：
Thomas F Schilling
金额：
$ 33.99万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9217590
关键词：
Address Adhesions Architecture Back Binding Proteins Biological Assay Cells Connective Tissue Data Defect Development Disease Elasticity Embryo Exercise Exposure to Extracellular Matrix Extracellular Matrix Proteins F-Actin Feeds Fibroblasts Filopodia Fluorescence Gene Expression Genetic Goals Head Human Image In Vitro Injury Integrins Ligaments Ligands Limb structure Maintenance Membrane Glycoproteins Mesoderm Methods Microscopy Modeling Mohawk Monitor Morphogenesis Muscle Muscle Contraction Musculoskeletal System Mutant Strains Mice Neural Crest Pharmacological Treatment Pharmacology Physiological Play Principal Investigator Process Production Regulation Research Role Signal Transduction Site Spatial Distribution Specific qualifier value Stem cells Structure Tendinopathy Tendon Injuries Tendon structure Testing Thrombospondins Transforming Growth Factor beta Transgenic Organisms Ursidae Family Zebrafish bone cell fate specification feeding genetic manipulation human stem cells in vivo imaging inhibitor/antagonist injury and repair loss of function mechanical force mechanical load mutant myogenesis novel overexpression progenitor programs public health relevance repaired response scleraxis skeletogenesis stem tendon development transcription factor

项目摘要

DESCRIPTION (provided by applicant): The formation of myotendinous junctions (MTJs) is a fundamental component of a functional musculoskeletal system. Muscles interact with tendons at their attachment sites, causing a reorganization of the extracellular matrix (ECM) into connective tissue structures that can bear the large forces exerted by muscle contraction. The transcription factors Scleraxis (Scx) and Mohawk (Mkx), as well as the membrane glycoprotein Tenomodulin (Tnmd), specify early tendon progenitors and regulate ECM production, and we recently discovered an ECM protein and Integrin (Itg) ligand called Thrombospondin-4b (Tsp4b) in zebrafish that is regulated by Scx and required for muscle attachment. How tendon progenitors reach sites of muscle attachment and influence ECM assembly and muscle adhesion at the MTJ remains unclear. The current proposal addresses these issues using the advantages of the zebrafish for in vivo imaging and genetic manipulation. The long-term goal of the proposed research is to understand the spatial dynamics of ECM assembly and cell fate specification in tendons and ligaments. Two primary hypotheses guide the research: 1) Mkx and Tnmd interact with Scx to control tenocyte morphogenesis and ECM assembly at MTJs, and 2) Itg and Tgfb signaling in response to mechanical load regulates Scx, Mkx and Tnmd expression during the formation of MTJs. Aim 1 is to visualize tendon progenitors in living wild-type, Mkx and Tnmd mutant embryos. Aim 2 is to study roles for Itg and Tgfb signaling in regulation of Scx, Mkx and Tnmd expression. Aim 3 is to study the roles of Itg and Tgfb signaling in response to mechanical load. Each aim combines novel genetic manipulation, fluorescence dynamics imaging and quantitative methods for physiological stimulation of muscles to get at the mechanisms of ECM assembly at these specialized connective tissue structures.

描述：肌齿状连接（MTJ）的形成是功能性musculostalM的底座成分，可以承受肌肉收缩施加的大力量。早期的肌腱祖细胞和常规的ECM产生，我们最近在斑马鱼中发现了一个由SCX定期的，ZEBRAFISH中的ECM蛋白质和整联蛋白（ITG）配体平静的血小板蛋白-4b（TSP4B），并需要肌肉的肌肉接触部位。组装和肌肉粘附尚不清楚当前的提案 @ Research的长期目标IS IS IS IS IS是长期目标。在肌腱和韧带中。 - 型，MKX和TNMD突变体胚胎。