Regulation of ubiquitin ligase genes in skeletal muscle

描述（由申请人提供）：肌肉损失或“萎缩”是许多不同情况的结果，包括：衰老，固定/卧床，代谢疾病，癌症和神经退行性疾病。到目前为止，还没有有效的药物来预防或治疗肌肉质量或力量的损失，或加速肌肉萎缩后的恢复。参与控制肌肉合成代谢和分解代谢过程的途径定义不清，因此药物开发的潜在靶点很少。然而，最近的数据表明，新的，肌肉特异性的E3泛素连接酶，MuRF1和MAFbx/Atrogin-1，是萎缩过程的关键调节因子。这两个基因在迄今为止测试的所有急性萎缩模型中都上调，表明类似的转录控制。在本提案中，MuRF-1和MAFbx启动子将在培养细胞和体内骨骼肌中进行功能表征，特别关注共识GRE和FOXO序列之间的相互作用。我们的数据将提供关于这些基因转录控制的关键信息，从而在诱导肌肉损失的条件下控制它们的表达。

DESCRIPTION (provided by applicant): Muscle loss or "atrophy" occurs as the result of a number of disparate conditions including: aging, immobilization/bedrest, metabolic diseases, cancer and neurodegenerative diseases. To date, there are no effective pharmacologic agents to prevent or treat the loss of muscle mass or strength, or to accelerate muscle recovery following atrophy. The pathways involved in controlling anabolic and catabolic processes in muscle are poorly defined, consequently there are few potential targets for drug development. Recent data, however, suggests that the novel, muscle specific E3 ubiquitin ligases, MuRF1 and MAFbx/Atrogin-1, are critical regulators of the atrophy process. Both genes are up-regulated in all acute atrophy models tested to date, suggesting similar transcriptional control. In this proposal, the MuRF-1 and MAFbx promoters will be functionally characterized in cultured cells and in skeletal muscles in vivo, with particular attention to the interaction between consensus GRE and FOXO sequences. Our data will provide critical information about the transcriptional control of these genes leading to means to control their expression under conditions that induce muscle loss.