Integrin Alleviation of Muscular Dystrophy

描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种毁灭性的致命肌肉萎缩疾病，仅在美国就影响近50,000名患者，目前尚无有效的治疗或治愈方法。DMD患者和MDX小鼠(DMD的小鼠模型)都有dystrophin基因突变，并且缺乏dystrophin蛋白。虽然受损的肌肉能够修复，但DMD患者的肌肉再生无法跟上肌肉损伤的步伐。卫星细胞是一种成体肌肉干细胞群体，可介导肌肉再生，治疗策略一直致力于提高这些细胞修复受损肌肉的能力。1721整合素是一种主要的层粘连蛋白受体，表达于卫星细胞、成肌细胞和血管平滑肌。我们的实验室最近表明，MDX小鼠体内17整合素的丢失会导致严重的肌肉营养不良，部分原因是肌肉修复能力降低。这些数据表明，1721整合素是营养不良肌肉的主要遗传修饰物。此外，DMD患者和MDX小鼠的血管功能降低。鉴于肌肉微血管和卫星细胞的密切联系，血管功能下降可能会对卫星细胞的激活、存活和肌肉再生产生负面影响。1721整合素在血管平滑肌细胞和成肌细胞中高度表达；然而，目前尚不清楚增强这些细胞中17整合素的表达是否会进一步预防DMD小鼠模型中的肌肉疾病。这项建议将检验这样一个假设，即靶向在成肌细胞或血管平滑肌中表达17整合素可以作为一种基于整合素的有效治疗肌营养不良症的方法。我们将在三个具体目标上检验这一假设。首先，使用小鼠和分离的缺乏17整合素的原代成肌细胞，我们将确定1721整合素在肌肉修复中的作用。其次，我们将确定增强成肌细胞中17整合素的表达是否可以改善成肌细胞的存活、植入和受损和营养不良肌肉的修复。最后，我们将确定增强17整合素在血管平滑肌中的表达是否可以改善营养不良小鼠的血管功能，减少肌肉病理。确定17整合素表达增强是否改善血管功能和肌肉再生，可能为杜兴和其他肌营养不良症的治疗提供基于整合素的新的靶向方法。与公共卫生相关。杜氏肌营养不良症是一种毁灭性的肌肉疾病，在美国有近5万名儿童受到影响。骨骼肌17整合素表达的增加已被证明对治疗这种疾病的小鼠模型有极大的好处。这项研究将使用转基因小鼠来研究1721整合素在肌肉修复中的作用，并确定在肌肉修复细胞或血管平滑肌中增加整合素的表达是否可以进一步改善基于整合素的肌营养不良症的治疗。

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a devastating lethal muscle wasting disease that affects nearly 50,000 patients in the US alone and for which there is no effective treatment or cure. Both DMD patients and mdx mice (the mouse model for DMD), have dystrophin gene mutations and lack the dystrophin protein. Although damaged muscle is capable of repair, muscle regeneration in DMD patients is unable to keep pace with muscle damage. Satellite cells are a population of adult muscle stem cells that mediate muscle regeneration and therapeutic strategies have been aimed at increasing the capacity of these cells to repair damaged muscle. The 1721 integrin is a major laminin receptor expressed in satellite cells, myoblasts and vascular smooth muscle. Our laboratory has recently shown that loss of the 17 integrin in mdx mice leads to severe muscular dystrophy which is caused in part by a reduced capacity for muscle repair. These data suggest the 1721 integrin is a major genetic modifier in dystrophic muscle. In addition DMD patients and mdx mice exhibit reduced vascular function. Given the close association of muscle microvasculature and satellite cells, reduced vascular function may negatively impact satellite cell activation, survival and muscle regeneration. The 1721 integrin is highly expressed in vascular smooth muscle cells and myoblasts; however it is unknown if enhancing 17 integrin expression in these cells will further prevent muscle disease in mouse models for DMD. This proposal will test the hypothesis that targeting 17 integrin expression in myoblasts or vascular smooth muscle can serve as an effective integrin-based therapy for muscular dystrophy. We will test this hypothesis in three Specific Aims. First, using mice and isolated primary myoblasts that lack the 17 integrin we will determine the role of the 1721 integrin in muscle repair. Second, we will determine if enhancing the expression of 17 integrin in myoblasts can improve myoblast survival, engraftment and repair of damaged and dystrophic muscle. Finally we will determine if enhanced 17 integrin expression in vascular smooth muscle can improve vascular function and reduce muscle pathology in dystrophic mice. Determining if enhanced 17 integrin expression improves vascular function and muscle regeneration may provide new targeted integrin-based approaches in the treatment of Duchenne and other muscular dystrophies. PUBLIC HEALTH RELEVANCE. Duchenne Muscular Dystrophy is a devastating muscle disease that affects nearly 50,000 children in the United States. Increased skeletal muscle expression of 17 integrin has been shown to be enormously beneficial to mouse models for this disease. This study will use transgenic mice to investigate the role of the 1721 integrin in muscle repair and determine if increasing integrin expression in muscle repair cells or vascular smooth muscle may further improve integrin-based therapies for muscular dystrophy.