Regulation of skeletal alpha actin expression during mu*

mu* 期间骨骼 α 肌动蛋白表达的调节

基本信息

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
项目类别：
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

项目摘要

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，它允许在身体不活动引起的萎缩后恢复质量。不幸的是，在某些情况下，例如衰老，高血压或糖尿病，骨骼肌通过增加肌肉质量而不会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，并确定在骨骼肌肉萎缩后无法再生长的条件下，机制是否功能失调。肌肉质量的增加受到多个级别的调节，包括转录，翻译和翻译后水平。尽管调节肌肉从萎缩回合中恢复的关键分子机制仍然不确定，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）已用于诱导骨骼肌肥大，以营救老年动物的肌肉肿块，并治疗神经肌肉疾病，例如肌营养不良症和肌营养性侧向硬化症。不幸的是，目前尚不清楚IGF-I如何影响骨骼肌的有益作用。当前，影响肌肉再生过程中基因表达的转录机制尚未完全定义，并且从未探索过IGF-I与这些机制的潜在相互作用。 IGF-I激活的机制对肌肉生物学领域的理解至关重要，因为由于包括癌症在内的IGF-I（包括癌症）的无需副作用，因此很难在人类医学中使用IGF-I。规避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，然后通过药理手段调节这些机制。具体的目标1将描述骨骼肌再生期间骨骼A-肌动蛋白基因转录激活所必需的顺式元素和转录因子。不幸的是，迄今为止，尚无研究检查从骨骼肌萎缩回收过程中调节任何基因转录激活的任何顺式元素和/或跨因素。具体目标2将确定IGF-I在骨骼肌再生过程中特定的顺式元素和转录因子的骨骼A-肌动蛋白基因转录激活的作用。总体目标是确定IGF-I在激活肌肉再生过程中的转录活性中的作用。