Dystrophin-glycoprotein complex in cardiomyopathy

描述（由申请人提供）：本申请的长期目标是了解遗传性心肌病的分子基础，特别是那些与糖糖异常-糖蛋白复合物组分突变相关的疾病。糖醛酸-糖蛋白复合物提供了从细胞骨架到细胞外基质的连接。这种复合物成分的突变，如三角肌聚糖，会导致隐性的肌肉萎缩症。有趣的是，同样的三角肌聚糖的杂合突变也可以引起扩张性心肌病，但没有肌肉萎缩症。这些突变的组织特异性的基础和肌糖聚糖相关扩张型心肌病背后的机制尚不清楚。此外，肌营养不良患者的糖基化异常聚糖酶突变，其活性是异常聚糖结合细胞外配体所必需的，也有较高的心肌病患病率。这一提议验证了细胞骨架和细胞外基质之间的联系的假设，即“通过糖异常蛋白，特别是在心肌细胞中，对心肌病的发展至关重要”。该研究将通过分离的肌肉细胞基因转移来测试δ肌聚糖突变对α -肌聚糖附着于跨膜复合物的显性阴性和组织特异性影响。此外，将在肌营养不良小鼠中测试肌营养不良蛋白糖基化与细胞外基质和心肌病发展的联系中的组织特异性作用。最后，将生成组织特异性基因靶向小鼠，以确定细胞骨架到基质通过糖醛酸异常的连接是否以组织特异性方式必要和充分地导致和解释DGC相关心肌病的发展。

DESCRIPTION (provided by applicant): The long term objective of this proposal is to understand the molecular basis of inherited cardiomyopathies, particular those associated with mutations in components of the dystroglycan-glycoprotein complex. The dystroglycan-glycoprotein complex provides a link from the cytoskeleton to the extracellular matrix. Mutations in components of this complex, such as delta sarcoglycan, cause recessive forms of muscular dystrophy. Interestingly, heterozygous mutations in the same delta sarcoglycan can also cause dilated cardiomyopathy without muscular dystrophy. The basis for the tissue specificity of these mutations and the mechanism behind sarcoglycan associated dilated cardiomyopathy is unclear. Furthermore, muscular dystrophy patients with mutations in enzymes that glycosylate dystroglycan and whose activity is necessary for dystroglycan to bind extracellular ligands, also have a high prevalence of cardiomyopathy. This proposal tests the hypothesis that the link between the cytoskeleton and the extracellular matrix 'through dystroglycan, specifically in cardiac myocytes, is critical 'to the development of cardiomyopathy. The proposed research will test the dominant-negative and tissue specific effects of delta sarcoglycan mutations on the attachment of alpha-dystroglycan to the transmembrane complex using isolated muscle cell gene transfer. In addition, the tissue specific role of dystroglycan glycosylation in the link to the extracellular matrix and the development of cardiomyopathy will be tested in the myodystrophy mouse. Finally, tissue specific gene targeted mice will be generated to determine if the link from cytoskeleton to matrix through dystroglycan, is necessary and sufficient in a tissue specific manner, to cause and explain the development of DGC associated cardiomyopathy.