GENETIC MODIFIERS AND CARDIOMYOPATHY

锰超氧化物歧化酶（MnSOD）是必需的， 体内产生的超氧化物的解毒。MnSOD 在CD 1背景下产生的缺陷小鼠迅速发展为 扩张型心肌病和代谢性酸中毒，10天内死亡 出生后然而，当-/-小鼠在混合环境中产生时， C57 BL/6和DBA/2 J的遗传背景， 至18天。不是心肌病，而是神经元缺失， 似乎是长寿-/-小鼠死亡的原因。这些 研究结果表明，可以调节 高水平的线粒体内超氧化物对 MnSOD缺陷小鼠心肌病的发展 在某些品系的小鼠中。这些修饰语的识别是 在设计治疗方法方面非常重要， 改善自由基诱导的线粒体损伤， 随之而来的组织损伤。因此，在具体目标I中，遗传 策略将被用来本地化这些修饰语，并确定 与修饰基因紧密连锁的遗传标记。的功能 的修饰等位基因，然后将在具体目标II研究， 组织学、生物化学和分子方法。

Manganese superoxide dismutase (MnSOD) is essential for the detoxification of intramitochondrially-generated superoxide. MnSOD deficient mice generated on the CD1 background quickly develop a dilated cardiomyopathy and metabolic acidosis and die within 10 days after birth. However, when the -/- mice were generated on a mixed genetic background of C57BL/6 and DBA/2J, an extended lifespan of up to 18 days was observed. Neuronal loss, rather than cardiomyopathy, appears to be the cause of death in the long-lived -/- mice. These findings indicate that genetic modifier(s) that can modulate the effects of high levels of intra-mitochondrial superoxide on the development of cardiomyopathy in the MnSOD deficient mice are present in certain strains of mice. The identification of these modifiers is of great importance in devising therapeutic approaches to the amelioration of free radical-induced mitochondrial damage and consequent tissue injury. Therefore, in Specific Aim I, genetic strategies will be used to localize these modifiers and to identify genetic markers closely linked to the modifier gene(s). The functions of the modifier alleles will then be studied in Specific Aim II by histological, biochemical and molecular approaches.