C/EBP, p300 and atrogin-1 in muscle wasting

描述（由申请人提供）：败血症期间和损伤后的肌肉萎缩至少部分由糖皮质激素介导，主要反映泛素-蛋白酶体依赖的蛋白质分解。最近的研究表明，新发现的泛素连接酶atrogin-1的基因表达在糖皮质激素作用下的萎缩肌肉中上调。其他研究表明，转录因子C/EBP β和δ的表达和活性增加，但尚不清楚C/EBP β和δ是否在肌肉萎缩中调节atroggin - 1基因。核辅因子p300在肌肉萎缩中基因调控的作用也是未知的。在拟建的项目中，我将测试以下假设：a)糖皮质激素激活了C/EBP和p300的表达和活性增加所导致的阿特罗激素-1基因；b)糖皮质激素诱导的C/EBP-atrogin-1基因激活级联至少在一定程度上导致肌肉萎缩。该项目很重要，因为它将进一步确定糖皮质激素相关肌肉萎缩的分子调控，例如败血症和严重损伤后的肌肉萎缩。使用培养的肌肉细胞将允许在基因水平上定义肌肉萎缩的机制。

DESCRIPTION (provided by applicant): Muscle wasting during sepsis and after injury is at least in part mediated by glucocorticoids and mainly reflects ubiquitin-proteasome-dependent protein breakdown. Recent studies suggest that the gene expression of the newly discovered ubiquitin-ligase atrogin-1 is upregulated in atrophying muscle by glucocorticoids. Other studies suggest that the expression and activity of the transcription factors C/EBP Beta and delta are increased but it is not known if C/EBP-Beta and delta regulate the atrogin-I gene in muscle wasting. The role of the nuclear cofactor p300 for gene regulation in atrophying muscle is also unknown. In the proposed project, I will test the hypotheses that a) glucocorticoids activate the atrogin-1 gene secondary to increased expression and activity of C/EBP and p300; and b) glucocorticoid-induced C/EBP-atrogin-1 gene activation cascade is at least in part responsible for muscle wasting. The project is important because it will further define the molecular regulation of glucocorticoid-related muscle wasting, such as seen in sepsis and after severe injury. The use of cultured muscle cells will allow for defining mechanisms of muscle wasting at the gene level.