Regulation of skeletal alpha actin expression during mu*

mu* 期间骨骼 α 肌动蛋白表达的调节

• 批准号: 7031397
• 负责人: ESPEN E SPANGENBURG
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-09 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031397
• 关键词: actins; atrophy; gastrocnemius muscle; gel mobility shift assay; gene deletion mutation; genetic promoter element; genetic regulation; genetic transcription; genetically modified animals; immobilization of body part; insulinlike growth factor; intermolecular interaction; laboratory mouse; longitudinal animal study; muscle pharmacology; musculoskeletal regeneration; myogenesis; phosphorylation; plasmids; site directed mutagenesis; striated muscles; transcription factor; transfection; tyrosine

DESCRIPTION (provided by applicant): Skeletal muscle regrowth is a fundamental process that allows the recovery of mass after a bout of atrophy induced by physical inactivity. Unfortunately, under some circumstances, such as aging, hypertension, or diabetes, the skeletal muscle does not respond to increases in mechanical load by increasing muscle mass. The long term objective is to determine the cellular/molecular mechanisms that regulate muscle regrowth under healthy conditions, and determine if the mechanisms are dysfunctional in conditions where skeletal muscle does not regrow after a bout of atrophy. Increases in muscle mass are regulated at multiple levels, including the transcriptional, translational, and posttranslational level. Although, key molecular mechanisms that regulate the recovery of muscle from a bout of atrophy remain undefined, it is well known that endogenous growth factors play an integral role in stimulating muscle growth. Recently, insulin-like growth factor (IGF-I) has been used to induce skeletal muscle hypertrophy, to rescue lost muscle mass in aged animals and to treat neuromuscular diseases such as muscular dystrophy and amyotrophic lateral sclerosis. Unfortunately, it is unclear how IGF-I is impacting beneficial effects on the skeletal muscle. Currently, the transcriptional mechanisms that impact gene expression during muscle regrowth are not completely defined, and further the potential interaction of IGF-I with these mechanisms has never been explored. The understanding of the mechanisms activated by IGF-I is of fundamental importance to the muscle biology field, since it will be difficult to use IGF-I in human medicine, due to the numerous undesired side effects of IGF-I, including cancer. One potential way to circumvent the side effects is to understand the cellular mechanisms by which IGF-I alters skeletal muscle, and then modulate these mechanisms through pharmacological means. Specific Aim 1 will delineate the cis elements and the transcription factors necessary for transcriptional activation of the skeletal a-actin gene during skeletal muscle regrowth. Unfortunately to date, no studies have examined any cis-elements and/or trans-factors that regulate transcriptional activation of any gene during recovery from a bout of skeletal muscle atrophy. Specific Aim 2 will determine the role IGF-I, has on the transcriptional activation of the skeletal a-actin gene through specific cis-elements and transcription factors during skeletal muscle regrowth. The overall goal is to determine the role IGF-I may have in activating transcriptional activity during muscle regrowth.

描述（由申请人提供）：骨骼肌再生是一个基本过程，可以在身体活动不足引起的萎缩后恢复质量。不幸的是，在某些情况下，如衰老、高血压或糖尿病，骨骼肌不会通过增加肌肉质量来响应机械负荷的增加。长期目标是确定在健康条件下调节肌肉再生的细胞/分子机制，并确定在骨骼肌萎缩后不能再生的条件下这些机制是否功能失调。肌肉质量的增加在多个水平上受到调节，包括转录、翻译和翻译后水平。尽管调节肌肉从萎缩中恢复的关键分子机制尚未确定，但众所周知内源性生长因子在刺激肌肉生长中起着不可或缺的作用。最近，胰岛素样生长因子（IGF-I）已被用于诱导骨骼肌肥大，挽救老年动物失去的肌肉质量，并治疗神经肌肉疾病，如肌营养不良症和肌萎缩性侧索硬化症。 不幸的是，目前还不清楚IGF-I如何影响骨骼肌的有益作用。目前，在肌肉再生过程中影响基因表达的转录机制尚未完全确定，而且IGF-I与这些机制的潜在相互作用从未被探索过。对IGF-I激活机制的理解对于肌肉生物学领域具有根本重要性，因为由于IGF-I的许多不期望的副作用，包括癌症，IGF-I将难以在人类医学中使用。避免副作用的一种潜在方法是了解IGF-I改变骨骼肌的细胞机制，然后通过药理学手段调节这些机制。具体目标1将描绘骨骼肌再生过程中骨骼α-肌动蛋白基因转录激活所必需的顺式元件和转录因子。不幸的是，迄今为止，没有研究已经检查了任何顺式元件和/或反式因子，调节任何基因的转录激活过程中恢复一回合的骨骼肌萎缩。特定目标2将确定IGF-I在骨骼肌再生期间通过特定顺式元件和转录因子对骨骼α-肌动蛋白基因的转录激活的作用。总体目标是确定IGF-I在肌肉再生过程中激活转录活性的作用。