Muscular Dystrophy Therapy by Increased Angiogenesis

描述(由申请人提供)：项目摘要/摘要Duchenne肌营养不良症(DMD)是一种进行性疾病，缺乏dystrophin蛋白会导致肌肉膜上的dystrophin桥丢失。最近的研究表明，dystrophin参与了血流调节，这在DMD中受到干扰，导致肌肉损伤增加。然而，血管生成在DMD治疗中的重要性尚未得到很好的解决。我们认为，给予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，我们最近创造了Flt-1杂合MDX小鼠(mdx：flt-1+/-)。MDX小鼠作为DMD的模型，血管内皮生长因子(VEGF)与Flt-1受体结合，负向调节血管生成。重要的是，与MDX：UTUN-/-：Flt-1+/+小鼠相比，MDX：UTUN-/-：Flt-1+/-三重突变小鼠的肌肉组织学有所改善，存活率显著提高。我们的项目将以这些初步数据为基础，更紧密地揭示血管生成增加最终如何影响MDX小鼠的DMD表型。此外，我们还将研究通过给予抗Flt-1多肽或针对Flt-1的shRNA来阻断Flt-1功能而增加的血管生成是否可以改善MDX和MDX：UTUN-/-小鼠的肌肉营养不良表型。 公共卫生相关性：项目叙述Duchenne肌肉营养不良症(DMD)是由dystrophin基因突变引起的，该基因通常起到维持肌膜完整性和防止收缩引起的损害的作用。通过使用促血管生成因子来增加血管的数量，并观察其对肌营养不良表型的影响，有可能减少肌肉纤维的损伤。我们预测，这些促血管生成因子将通过增加缺乏血液的营养不良肌肉中的血管密度来帮助开发治疗DMD的新疗法。

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. PUBLIC HEALTH RELEVANCE: Project Narrative Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene, which normally functions to maintain muscle membrane integrity and prevent contraction-induced damage. It may be possible to reduce muscle fiber damage by using pro-angiogenic factors to increase the number of blood vessels and observe the resultant effects on the muscular dystrophy phenotype. We predict that these pro-angiogenic factors will assist development of new therapies for DMD via increased vascular density in blood starved dystrophic muscles.