Molecular and Cellular Therapies for Muscular Dystrophy

肌营养不良症的分子和细胞疗法

基本信息

批准号：
8233488
负责人：
STANLEY C FROEHNER
金额：
$ 122.12万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233488
关键词：
Accounting Acids Advisory Committees Alpha-glucosidase Autologous Biological Assay CMV promoter Canis familiaris Cell Culture Techniques Cell Therapy Cell Transplantation Cells Collaborations Complex Core Facility Data Desmin Development Donor person Down-Regulation Duchenne muscular dystrophy Dystrophin Emery-Dreifuss Muscular Dystrophy Engraftment Exercise Extracellular Matrix Fatigue Fibroblasts Funding Gene Expression Gene Transfer Genes Genetic Glycogen storage disease type II Goals Hematopoietic Human Immunodeficient Mouse In Vitro Individual Injury Kinetics Knockout Mice Knowledge Laboratories Lamin Type A Lentivirus Vector Lesion Limb structure Link M-cadherin MM form creatine kinase Mesenchymal Stem Cells Methods MicroRNAs Modeling Molecular Mononuclear Mus Muscle Muscle Cells Muscle Fibers Muscle function Muscle satellite cell Muscular Dystrophies Mutate Mutation Myoblasts Myocardium Myopathy Natural regeneration Nerve Degeneration Neuroglia Nuclear Lamin Pericytes Pharmaceutical Preparations Phenotype Population Probability Production Progress Reports Protein Isoforms Proteins Publications RNA Reagent Regulation Reporter Research Design Respiratory Diaphragm Retinal Retinoblastoma Protein Role Sarcolemma Severities Signal Pathway Signal Transduction Signaling Protein Skeletal Muscle Source Stem cells Study Subject System Tamoxifen Testing Therapeutic Therapeutic Uses Time Tracer Transgenic Mice Transgenic Organisms Translations Transplantation Utrophin Work Xenograft procedure aquaporin 4 base beta catenin caveolin-3 cholesterol trafficking disease phenotype dystrobrevin gene therapy genetic manipulation human ITGA7 protein human disease human embryonic stem cell in vivo interest mdx mouse meetings member migration mouse model muscle degeneration muscle regeneration myogenesis palmitoylation prevent programs public health relevance reconstitution research study satellite cell stem cell therapy syntrophin therapeutic protein transduction efficiency vector

项目摘要

DESCRIPTION (provided by applicant): The muscular dystrophies, many caused by mutations in genes encoding proteins of the dystrophin complex, are among the most prevalent and devastating human diseases. No cures exist and current treatments that slow muscle degeneration are largely ineffective. The goal of this application is to apply basic knowledge of several muscular dystrophies to developing therapeutic approaches. In project 1, Jeffrey Chamberlain will isolate alternative types of myogenic stem cells, correct the primary genetic lesion in these cells by gene transfer, and explore the use of such cells for transplantation into syngeneic, dystrophic mice. He will generate myogenic stem cells from dystrophic muscle fibroblasts and explore their ability to generate new muscle tissue in vitro and in vivo and explore the therapeutic use of pericytes isolated from dystrophic muscle. In project 2, Stephen Tapscott will expand the cell therapy approach by examining muscle cell transplantation in the canine model of muscular dystrophy. Enhancement of migration and engraftment of transplanted donor cells will be explored by modulating signaling pathways and extracellular matrix components and genetic manipulations. Finally, specific muscle derived cell populations will be compared for their ability to reconstitute canine skeletal muscle in vivo. In project 3, Stephen Hauschka will modify muscle-specific regulatory cassettes to provide high expression in human muscle cultures. Modified cassettes will then be tested in vivo for expression of therapeutic proteins after AAV and Lentiviral delivery to human muscle xenografts in immunodeficient mice. Clonal satellite cell assays and analysis of human muscle fiber regeneration following xenograft injury will determine whether the satellite cell pool has been stably transduced. In project 4, Stanley Froehner will study a new compensatory gene, NPC1, which markedly reduces the severity of the dystrophic phenotype in mdx mouse muscle. The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories.

描述（由申请人提供）：肌肉营养不良，许多是由编码肌营养不良蛋白复合物蛋白质的突变引起的，是最普遍和毁灭性的人类疾病之一。不存在治疗方法，当前肌肉变性的治疗基本上是无效的。该应用的目的是将几种肌肉营养不良的基本知识应用于开发治疗方法。在项目1中，Jeffrey Chamberlain将通过基因转移校正这些细胞中的主要遗传病变的替代类型，并探索使用这种细胞将这种细胞移植到合元性，营养不良小鼠中。他将从营养不良的肌肉成纤维细胞中产生肌源性干细胞，并探索它们在体外和体内产生新的肌肉组织的能力，并探索从营养不良肌肉中分离出的周细胞的治疗用途。在项目2中，斯蒂芬·塔普斯科特（Stephen Tapscott）将通过检查肌肉营养不良犬模型中的肌肉细胞移植来扩展细胞疗法。通过调节信号通路和细胞外基质组件和遗传操作，将探索移植供体细胞的迁移和植入的增强。最后，将比较特定的肌肉衍生细胞群，以便在体内重新构成犬骨骼肌的能力。在项目3中，斯蒂芬·豪施卡（Stephen Hauschka）将修改肌肉特异性的调节盒，以在人类肌肉培养物中提供高表达。然后，将在体内测试改性盒，以在AAV和慢病毒递送到免疫缺陷小鼠中人类肌肉异种移植后表达治疗蛋白。异种移植后的克隆卫星细胞测定和人类肌肉纤维再生的分析将决定卫星细胞池是否已稳定转导。在项目4中，斯坦利·弗罗纳（Stanley Froehner）将研究一种新的补偿基因NPC1，该基因显着降低了MDX小鼠肌肉中营养不良表型的严重程度。将研究NPC1表型改善的机理及其对LGMD的适用性。两个核心设施将为参与的实验室服务。