MECHANISM OF CARDIOMYOPATHY IN SARCOGLYCAN DEFICIENCY

肌聚糖是一种肌营养不良蛋白相关蛋白复合体，它的突变会导致人类的心肌病和肌肉营养不良。通过基因打靶，我们产生了缺乏不同肌糖亚单位的小鼠，以更好地了解这些蛋白丢失导致膜不稳定和心肌损伤的机制。γ-肌聚糖和Delta-肌聚糖是高度相关的35kD跨膜蛋白。缺乏这些肌聚糖的小鼠会患上心肌病，并表现出膜缺陷，这是这些基因突变的人类所特有的。γ-肌聚糖在心肌和骨骼肌中大量表达，然而缺乏γ-肌聚糖的小鼠似乎出现了与缺乏β-肌聚糖的小鼠相似的平滑肌血管变化。因此，这种缺陷可能是原发于心肌细胞的肌聚糖丢失的次要后果。为了研究这一点，我们将比较缺乏伽马或三角洲肌聚糖的小鼠。我们将挽救肌肉中表达的Delta-肌聚糖。我们将研究一氧化氮合酶的作用，因为在没有dystrophin的情况下，非对抗性血管收缩已被确定为异常血管张力的中介。最后，我们将通过研究其他心肌病模型来研究心肌细胞退行性变是否会导致血管变化。

Mutations in sarcoglycan, a dystrophin-associated protein complex, cause cardiomyopathy and muscular dystrophy in humans. Through gene targeting, we have generated mice lacking different sarcoglycan subunits to understand better the mechanism by which the loss of these proteins produces membrane instability and cardiac muscle damage. Gamma-sarcoglycan and delta-sarcoglycan are highly related 35 KD, transmembrane proteins. Mice lacking either these sarcoglycans develop cardiomyopathy and show membrane defects characteristic of those seen in humans with mutations in these genes. Gamma-sarcoglycan is expressed exlusively in cardiac and skeletal muscle, yet mice lacking gamma-sarcoglycan appear to have smooth muscle vascular alterations similar to those seen in mice lacking delta-sarcoglycan. Thus, such defects may be a secondary consequence of the primary loss of sarcoglycan in the cariomyocyte. To investigate this, we will compare mice lacking gamma- or delta-sarcoglycan. We will rescue smooth muscle expression of delta-sarcoglycan. We will investigate the role of nitric oxide synthase since unopposed vasoconstriction has been identified as a mediator of abnormal vascular tone in the absence of dystrophin. Lastly, we will study whether cardiomyocyte degeneration produces vascular changes by studying other models of cardiomyopathy.