In vivo role of the fibroblast in muscular dystrophy

成纤维细胞在肌营养不良症中的体内作用

基本信息

批准号：
10377963
负责人：
Jeffery D Molkentin
金额：
$ 34.63万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377963
关键词：
Address Affect Agreement Alleles Award Basal lamina Blocking Antibodies Calcium Cardiac Myocytes Cell membrane Cell physiology Cells Cessation of life Cicatrix Collagen Complex Contractile Proteins Contracture Data Development Disease Disease Progression Disease model Dropout Drosophila genus Dystrophin Extracellular Matrix Fibrillar Collagen Fibroblasts Fibrosis Genetic Genetic Models Glycoproteins Goals Growth Factor Hand Heart Hereditary Disease Homeostasis Human Immune Inflammatory Intuition Knowledge Lead MADH2 gene MAP Kinase Gene Mediating Mediator of activation protein Membrane Messenger RNA Molecular Mus Muscle Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Muscular Dystrophies Mutation Myocardium Myofibroblast Myopathy Natural regeneration Necrosis Onset of illness Organ Pathologic Pathology Pathway interactions Patients Pharmacological Treatment Physiological Play Process Production Proteins Publications Receptor Signaling Regenerative capacity Role Sarcolemma Severity of illness Signal Pathway Signal Transduction Skeletal Muscle Striated Muscles System TGFBR2 gene Testing Tissues Transforming Growth Factor beta Receptors Transforming Growth Factors alpha Actin cell type chemokine cytokine delta Sarcoglycan functional decline genetic approach genetic manipulation genomic locus in vivo innovation mdx mouse mouse model muscle degeneration muscle necrosis muscular dystrophy mouse model mutant novel novel therapeutics p38 Mitogen Activated Protein Kinase periostin premature regenerative release factor repaired response side effect skeletal sound stem cells tool wasting

项目摘要

Abstract The muscular dystrophies are inherited disorders that largely affect striated muscle tissue resulting in progressive muscle weakness, wasting, and in many instances, premature death. Many characterized mutations in humans that cause muscular dystrophy (MD) result from alterations in structural attachment proteins that affix the underlying contractile proteins to the basal lamina, providing rigidity to the skeletal muscle cell membrane (sarcolemma). Loss of select attachment proteins in the dystrophin-glycoprotein complex (DGC) permits contraction-induced membrane tears and influx of calcium that causes cellular degeneration and necrosis of muscle fibers. During this necrotic process cytokines, chemokines and growth factors are released as part of the inflammatory and repair process, although induction of fibrosis and scarring are an unwanted side effect that worsens disease. One prominent cytokine is transforming growth factor-β (TGFβ) that serves a master regulator of the fibrotic response and worsening of muscle pathology in MD. While fibroblasts are directly regulated by TGFβ, no one has yet to examine the function of the fibroblast in skeletal muscle directly in vivo, as a mediator or fibrosis and muscular dystrophy. Here we generated a unique genetic model in the mouse that will selectively modulate the activity of the cardiac and skeletal muscle fibroblast in vivo and in dystrophic mouse models of disease. Thus, here we will test the novel hypothesis that myofibroblasts play a selective role in mediating fibrosis and tissue remodeling in heart and skeletal muscle in response to cellular dropout from MD, while resident myofibers and cardiomyocytes in their respective tissues underlie physiologic ECM / collagen production and basal lamina production during development and as part of ongoing homeostasis. The application has 2 comprehensive specific aims: 1) To genetically parse the role of myofibroblasts in skeletal muscle and heart during MD in the mouse, 2) To examine how TGFβ, SMAD2/3 and p38α signaling mediate disease in MD through the myofibroblast in vivo. The application will attempt to definitively address the function of the activated fibroblast (myofibroblast) in muscle during MD disease onset and progression. It will also attempt to elucidate the importance of TGFβ signaling in mediating myofibroblast formation and disease activity in vivo, as both canonical and non- canonical pathways will be genetically dissected.

抽象的肌肉营养不良是遗传性疾病，在很大程度上影响肌肉组织，导致渐进的肌肉无力，浪费，在许多情况下，过早死亡。许多人描述了引起肌肉营养不良（MD）的人类突变是由于结构附着的改变而导致的将基本收缩蛋白粘贴到碱性薄片上的蛋白质，为骨骼提供刚性肌肉细胞膜（肌膜）。肌营养不良蛋白中选择附着蛋白的损失复合物（DGC）允许合同引起的膜撕裂和钙的影响，导致细胞肌肉纤维的变性和坏死。在这种坏死过程中细胞因子，趋化因子和生长尽管纤维化诱导和疤痕是一种不必要的副作用，使疾病恶化。一个突出的细胞因子是转化生长因子-β （TGFβ）为MD中的纤维化反应和肌肉病理的担忧提供了主调节剂。虽然成纤维细胞直接受TGFβ调节，但没有人尚未检查成纤维细胞在直接在体内作为介体或纤维化和肌肉营养不良的骨骼肌。在这里，我们产生了一个独特的小鼠中的遗传模型将选择性调节心脏和骨骼肌肉的活性体内和营养不良小鼠疾病模型的成纤维细胞。那，我们将在这里检验新的假设肌纤维细胞在介导纤维化和组织重塑中起选择性作用肌肉响应MD的细胞辍学，而居民肌纤维和心肌细胞的肌肉各自的组织是生理ECM /胶原蛋白产生和基本薄片生产的基础的组织发展和作为正在进行的稳态的一部分。该应用程序具有2个全面的特定目标：1）从遗传上解析肌纤维细胞在小鼠中MD期间骨骼肌和心脏中的作用，2）检查MD中TGFβ，SMAD2/3和P38α信号中位数疾病是如何通过体内的肌纤维细胞。该应用程序将尝试确切地解决激活的成纤维细胞（肌纤维细胞）的功能 MD疾病发作和进展过程中的肌肉。它还将尝试阐明TGFβ的重要性在体内介导肌纤维细胞形成和疾病活性的信号传导，作为规范和非 - 规范途径将被遗传解剖。