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Ablation of Non-Myogenic Progenitor Cells as a New Therapeutic Approach to Duchenne Muscular Dystrophy

消融非肌源性祖细胞作为杜氏肌营养不良症的新治疗方法

基本信息

批准号：
10013124
负责人：
Johnny Huard
金额：
$ 14.92万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-09 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013124
关键词：
Ablation Acute Address Adipocytes Adipose tissue Adverse effects Affect Age Animal Model Animals Area Birth Cell Culture Techniques Cell Differentiation process Cell physiology Cells Chronic Chronic Disease Clinical Data Development Disease Disease Progression Drug Targeting Duchenne muscular dystrophy Dystrophin Fatty acid glycerol esters Fibroblasts Fibrosis Functional disorder Genetic Genetic Diseases Goals Hormonal Human Imatinib In Vitro Incidence Infiltration Inflammation Injury Intervention Investigational Therapies Knockout Mice Laboratories Lesion Measures Mediating Modeling Mus Muscle Muscle Cells Muscle Fibers Muscle Weakness Muscle function Muscular Dystrophies Mutation Myocardium Pathogenesis Pathogenicity Pathologic Pathology Patients Peptides Pharmaceutical Preparations Pharmacology Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor alpha Receptor Population Prednisone Proliferating Protein Tyrosine Kinase Reporting Research Severities Site Skeletal Muscle Source Standardization Steroid therapy Steroids Stromal Cells Suicide Gene Therapy Techniques Technology Testing Therapeutic Thymidine Kinase TimeLine Tissues Utrophin Virus cell type experience gene correction gene therapy genetic approach inhibitor/antagonist lipid biosynthesis mesenchymal stromal cell mouse model muscle regeneration muscle strength novel novel strategies novel therapeutic intervention progenitor promoter recruit restoration sarcopenia satellite cell side effect skeletal muscle wasting standard of care stem cells suicide gene targeted treatment therapeutic target therapy development tissue regeneration transgenic suicide gene

项目摘要

Abstract Duchenne muscular dystrophy (DMD) is a deadly genetic disease characterized by a lack of dystrophin expression, resulting in progressive weakening and wasting of skeletal and cardiac muscles. Currently, there is no cure for DMD. The approved hormonal treatments have side effects and delay the disease progression only transiently. The emerging gene correction strategies, although effective in mouse models, are likely to be of limited immediate value to patients due to issues associated with virus-mediated gene therapy. Therefore, new approaches to suppress the disease progression are needed. Myogenic muscle progenitor cells (MPCs), also known as satellite cells, become dysfunctional (reduced proliferation and differentiation capacities) as disease progresses, coincidentally with reduced muscle regeneration, aggravating fatty infiltration, and fibrotic tissue accumulation in skeletal muscle. Mesenchymal stromal cells (MSCs) are non-myogenic progenitors of fibroblasts and adipocytes. We and others have reported that MSCs get activated during the disease progression in DMD and turn into fibroadipogenic progenitors (FAPs) that proliferate, induce MPC dysfunction and contribute to muscle pathology. Our preliminary data indicates that FAPs express markers of adipocyte progenitors, also known as adipose stromal cells (ASCs), the MSCs derived from fat tissue, suggesting ASCs as a source of FAPs. The goal of this application is to test whether DMD pathogenesis can be delayed via depletion of MSC-derived FAPs in the mouse model. In Aim 1, an inducible genetic ablation of proliferating MSC will be performed using a suicide transgene. In Aim 2, pharmacological ablation will be performed with a hunter-killer peptide targeting ASCs. We will test if DMD progression, measured as MPC dysfunction, fatty infiltration, fibrotic tissue accumulation, and the resulting loss of skeletal muscle function, can be suppressed by these experimental treatments. We predict that ablation of FAPs derived from MSCs/ASCs from the dystrophic milieu will delay MPC depletion and DMD progression. Information obtained from these studies will help develop new therapeutic approaches for treating muscular dystrophy.

摘要杜氏肌营养不良症（DMD）是一种致命的遗传性疾病，其特点是缺乏抗肌萎缩蛋白表达，导致骨骼肌和心肌的进行性弱化和消耗。目前还没有治愈DMD的方法。批准的激素治疗有副作用，只能延缓疾病进展短暂的新兴的基因校正策略，虽然在小鼠模型中有效，但可能是有限的，由于与病毒介导的基因治疗相关的问题，因此，新方法来抑制疾病的发展。肌源性肌肉祖细胞（MPCs），也称为卫星细胞，随着疾病的进展而变得功能障碍（增殖和分化能力降低），与此同时，肌肉再生减少，加重脂肪浸润和纤维化组织积累，骨骼肌间充质基质细胞（MSC）是成纤维细胞和脂肪细胞的非肌源性祖细胞。我们和其他人已经报道，在DMD的疾病进展过程中，MSC被激活，并变成纤维脂肪生成祖细胞（FAP）增殖，诱导MPC功能障碍并导致肌肉病理学。我们的初步数据表明，FAP表达脂肪祖细胞的标志物，也称为脂肪祖细胞。基质细胞（ASC），即来源于脂肪组织的MSC，表明ASC是FAP的来源。这个目标本申请旨在测试DMD发病机制是否可以通过消耗DMD中MSC衍生的FAP来延迟。小鼠模型在目的1中，将使用自杀性细胞因子进行增殖MSC的诱导性基因消融。转基因。在目标2中，将使用靶向ASC的猎人杀伤肽进行药理学消融。我们将测试DMD进展，测量为MPC功能障碍、脂肪浸润、纤维化组织积聚，所导致的骨骼肌功能丧失可以通过这些实验性治疗来抑制。我们预测来自营养不良环境的MSC/ASC衍生的FAP的消融将延迟MPC耗竭和DMD，进展从这些研究中获得的信息将有助于开发新的治疗方法，肌肉萎缩症