MECHANISM OF CARDIOMYOPATHY IN SARCOGLYCAN DEFICIENCY

肌聚糖（一种肌营养不良蛋白相关蛋白复合物）的突变会导致人类心肌病和肌营养不良。通过基因靶向，我们产生了缺乏不同肌聚糖亚基的小鼠，以更好地了解这些蛋白质的丢失导致膜不稳定和心肌损伤的机制。 γ-肌聚糖和δ-肌聚糖是高度相关的35 KD跨膜蛋白。 缺乏这些肌聚糖的小鼠会发生心肌病，并表现出这些基因突变的人类所见的膜缺陷特征。γ-肌聚糖仅在心肌和骨骼肌中表达，但缺乏γ-肌聚糖的小鼠似乎具有与缺乏δ-肌聚糖的小鼠中所见相似的平滑肌血管改变。 因此，这种缺陷可能是肌聚糖在心肌细胞中的主要损失的继发性后果。 为了研究这一点，我们将比较缺乏γ-或δ-肌聚糖的小鼠。 我们将拯救平滑肌δ-肌聚糖的表达。 我们将研究一氧化氮合酶的作用，因为无对抗性的血管收缩已被确定为一个介导的异常血管紧张度在缺乏肌营养不良蛋白。 最后，我们将通过研究其他心肌病模型来研究心肌细胞变性是否会引起血管变化。

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.