通过增加血管生成治疗肌营养不良症-猫眼课题宝

通过增加血管生成治疗肌营养不良症

批准号：

8729809

负责人：

ATSUSHI ASAKURA

金额：

$7.4万

依托单位：

UNIVERSITY OF MINNESOTA

依托单位国家：

美国

项目类别：

财政年份：

2012

资助国家：

美国

项目状态：

已结题

起止时间：

2012-08-01 至 2015-07-31

来源：

https://reporter.nih.gov/project-details/8729809

关键词：

Address Adult Affect Angiogenic Factor Binding Blood Vessels Blood flow Cell Membrane Permeability Clinical Connective Tissue Data Disease Duchenne muscular dystrophy Dystrophin Dystrophin-Associated Protein Complex Embryo Endothelial Cells Fibrosis Gene Deletion Gene Expression Genes Goals Histology Histopathology Housing Human Injection of therapeutic agent Intramuscular Injections Intraperitoneal Injections Knowledge Laboratories Lead Link Membrane Modeling Mus Muscle Muscle Fibers Muscle function Muscle satellite cell Muscular Dystrophies Mutant Strains Mice Myopathy Natural regeneration Neuromuscular Diseases Newborn Infant Pathology Patients Peptides Phenotype Production Proteins Publications Regulation Reporting Research Skeletal Muscle Survival Rate Testing Utrophin Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular Smooth Muscle Vascular blood supply Work abstracting angiogenesis base calcification density gene therapy improved knockout gene male mdx mouse muscle regeneration muscular dystrophy mouse model mutant novel receptor repaired satellite cell small hairpin RNA

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中文摘要

翻译

描述（由申请人提供）：项目摘要/摘要杜氏肌营养不良症（DMD）是一种进行性疾病，其中肌营养不良蛋白的缺失导致肌膜上肌营养不良蛋白桥的缺失。最近的工作表明，肌营养不良蛋白参与血液流动调节，这是在DMD干扰，并导致增加肌肉损伤。然而，血管生成在DMD治疗中的重要性尚未得到很好的解决。我们建议，管理促血管生成因子可以恢复肌肉纤维和血管。为了揭示神经肌肉疾病和血管生成之间的关系，我们最近创建了Flt-1杂合mdx小鼠（mdx：Flt- 1+/-）。mdx小鼠用作DMD的模型，并且血管内皮生长因子（VEGF）与Flt-1受体结合以负调节血管生成。最近，我们的工作揭示了mdx：Flt-1+/-小鼠除了改善的肌肉病理和功能之外还显示出血管数量增加（Verma等人，2010年）。Utrophin缺陷型mdx小鼠（mdx：utrn-/-）显示出比mdx小鼠更严重的表型，并且mdx：utrn-/-小鼠更接近于人DMD表型。重要的是，与mdx：utrn-/-：Flt-1 +/+小鼠相比，mdx：utrn-/-：Flt-1+/-三重突变小鼠显示出改善的肌肉组织学和显著更高的存活率。我们的项目将建立在这些初步数据的基础上，以更密切地揭示血管生成增加最终如何影响mdx小鼠的DMD表型。此外，我们将检查通过给予阻断Flt-1功能的抗Flt-1肽或Flt-1 shRNA提供的血管系统增加是否可以改善mdx和mdx：utrn-/-小鼠的肌肉萎缩表型。

英文摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract Duchenne Muscular Dystrophy (DMD) is a progressive disorder in which the absence of the dystrophin protein results in loss of the dystrophin bridge at the muscle membrane. Recent work demonstrates the involvement of dystrophin in blood flow regulation, which is disturbed in DMD and causes increased muscle damage. However, the importance of angiogenesis in DMD treatment has not yet been well addressed. We propose that administration of pro-angiogenic factors can restore muscle fibers and blood vessels. To reveal the relationship between neuromuscular disease and angiogenesis, we recently created Flt-1 heterozygous mdx mice (mdx:Flt- 1+/-). mdx mice serve as a model for DMD, and vascular endothelial growth factor (VEGF) binds with Flt-1 receptors to negatively regulate angiogenesis. Recently, our work revealed that the mdx:Flt-1+/- mice display an increased number of blood vessels in addition to improved muscle pathology and function (Verma et al., 2010). Utrophin deficient mdx mice (mdx:utrn-/-) display a more severe phenotype than mdx mice, and the mdx:utrn-/- mice more closely resemble a human DMD phenotype. Importantly, mdx:utrn-/-:Flt-1+/- triple mutant mice display improved muscle histology and significantly higher survival rates compared to mdx:utrn-/-:Flt-1+/+ mice. Our project will build on these preliminary data to more closely reveal how increased angiogenesis ultimately affects the DMD phenotype in mdx mice. In addition, we will examine whether increased vasculature provided by the administration of an anti-Flt-1 peptide or shRNA for Flt-1 that block Flt-1 function can improve the muscular dystrophic phenotype in mdx and mdx:utrn-/- mice.

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