Integrin Alleviation of Muscular Dystrophy

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种毁灭性的致命肌肉萎缩疾病，仅在美国就影响了近50,000名患者，并且没有有效的治疗或治愈方法。DMD患者和mdx小鼠（DMD小鼠模型）都有肌营养不良蛋白基因突变，缺乏肌营养不良蛋白。虽然受损的肌肉能够修复，但DMD患者的肌肉再生跟不上肌肉损伤的速度。卫星细胞是一种介导肌肉再生的成体肌肉干细胞，治疗策略旨在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，在卫星细胞、成肌细胞和血管平滑肌中表达。我们的实验室最近表明，mdx小鼠中17整合素的缺失会导致严重的肌肉萎缩症，部分原因是肌肉修复能力下降。这些数据表明1721整合素是营养不良肌肉的主要遗传修饰因子。此外，DMD患者和mdx小鼠表现出血管功能下降。鉴于肌肉微血管和卫星细胞的密切联系，血管功能的降低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表达；然而，在DMD小鼠模型中，增强这些细胞中的17整合素表达是否会进一步预防肌肉疾病尚不清楚。这一提议将验证靶向17整合素在成肌细胞或血管平滑肌中的表达可以作为一种有效的基于整合素的肌营养不良治疗的假设。我们将在三个具体目标中检验这一假设。首先，利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17整合素在成肌细胞中的表达是否可以改善成肌细胞的存活、植入以及受损和营养不良肌肉的修复。最后，我们将确定在营养不良小鼠血管平滑肌中增强17整合素表达是否可以改善血管功能并减少肌肉病理。确定17整合素表达增强是否能改善血管功能和肌肉再生，可能为治疗杜氏肌营养不良症和其他肌营养不良症提供新的靶向整合素方法。公共卫生相关性。杜氏肌营养不良症是一种毁灭性的肌肉疾病，影响着美国近5万名儿童。骨骼肌17整合素表达的增加已被证明对这种疾病的小鼠模型非常有益。本研究将使用转基因小鼠研究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表达是否可以进一步改善基于整合素的肌营养不良治疗。

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.