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Treatment of Muscular Dystrophy by Increased Angiogenesis

通过增加血管生成治疗肌营养不良症

基本信息

批准号：
9303307
负责人：
Mayank Verma
金额：
$ 4.85万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303307
关键词：
Adipose tissue Affect Affinity Age Alleles Apoptosis Automobile Driving Biology Blood Vessels Blood capillaries Blood flow Brain Cell Proliferation Cells Childhood Coculture Techniques Connective Tissue Data Development Duchenne muscular dystrophy Dystrophin Embryo Endothelial Cells Endothelium Excision Fiber Genes Goals Heart Hereditary Disease Histologic In Vitro Injection of therapeutic agent Injury Investigational Therapies Knock-out Knockout Mice Knowledge Lead Liver Mediating Mission Modeling Molecular Mus Muscle Muscle Fibers Muscle satellite cell Muscular Dystrophies Myopathy National Institute of Arthritis and Musculoskeletal and Skin Diseases Natural regeneration Nerve Degeneration Onset of illness Outcome Palliative Care Pathogenesis Pathologic Neovascularization Pathology Perfusion Peripheral arterial disease Phenotype Population Proteins Publications Reporting Role Signal Transduction Skeletal Muscle Smooth Muscle Staining method Stains Stem cells Steroid therapy Steroids Supportive care System Tamoxifen Tissues VEGF Trap Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Work angiogenesis base cancer therapy capillary density exhaust functional improvement improved in vivo insight knock-down knockout gene mdx mouse migration muscle regeneration novel prevent promoter public health relevance receptor repaired response satellite cell self-renewal targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a progressive neurodegenerative muscle disease caused by the absence of the dystrophin protein. Currently, there is no cure for DMD, and treatment is confined to steroids and palliative therapy. Although dystrophin is a major component of the skeletal muscle, its role in the vasculature has only recently been appreciated. The long-term goal of this project is to elucidate the role of the vasculature and muscle stem cells and their interactions as it pertains to muscle pathology in DMD. We have previously shown that developmentally increased angiogenesis and capillary density in DMD model mdx mice by deleting one allele for the Vascular Endothelial Growth Factor (VEGF) receptor, Flt-1 gene. Interestingly, this led to an increase in muscle stem cells (satellite cells) and improved histological and contractile function. [These data suggest tha increasing the vasculature can increase the satellite cell pool and ameliorate the dystrophic phenotype seen in mdx mice. However, the mechanism behind this interaction remains unclear. This proposal will attempt to fill this gap in knowledge. First, we will identify the VEGF receptor expressed on muscle stem cells and determine the effects of exogenous VEGF on these cells in vitro. Second, we will utilize endothelial cell/muscle stem cell co-culture systems to determine whether endothelial cells can modulate quiescence, proliferation, and differentiation in muscle stem cells. Lastly, we will utilize Cre-loxP-mediated conditional Flt-1 gene knockout mice to examine whether complete post-natal excision of Flt-1 gene results in increased capillary density in the skeletal muscle and an improvement in the dystrophic phenotype in the mdx mice. ] This will serve as a proof of concept to see whether Flt-1 can be used as a drug target for the treatment of DMD. This information can have applications beyond DMD as VEGF and its receptors are also under investigation for the treatment of peripheral artery disease, ischemic injury, as well as anti-cancer therapy. Outcomes from these three independent Aims will directly lead to the development of pro-angiogenic treatment options for DMD and therefore reflects the mission of NIAMS.