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Failed rescue of old skeletal muscle from atrophy

挽救老旧骨骼肌萎缩失败

基本信息

批准号：
6759346
负责人：
FRANK W BOOTH
金额：
$ 29万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-15 至 2006-07-31
项目状态：
已结题

项目摘要

A common clinical problem is that in many nursing homes there are mobile and functioning aged individuals who, upon being subjected to one or more periods of immobility due to illness or injury, are unable to return back to mobility. Even with extensive rehabilitative therapy, many of these individuals are unable to recover to preinjury functioning levels. An animal model mimics this human condition. Both young and old rats who undergo a 10-day period of hindlimb immobilization exhibit disuse atrophy, but only skeletal muscle from young rats successfully regrows from this disuse atrophy as old muscle had no regrowth after 77 days of recovery. Hypothesis 2 reads: "Ten of the 200 mRNAs corresponding to growth factors, growth factor receptors, or post-receptor signaling that are present on the employed microarray will differ between young and old rats during the failure of old skeletal muscle to rescue itself from immobilization-induced atrophy during reloading. Specific aim 1 will identify a pool of mRNAs associated with the failure of old skeletal muscle to rescue itself from immobilization-induced atrophy during reloading. Another observation is that short-term IGF-I application will rescue the failure of old muscle to regrow after disuse atrophy. However, this effect is only transient as continued IGF-I application to old muscle depletes remaining satellite cell proliferations and muscle wastes. Thus, all defective growth factor responses must be identified. Specific aim 2 will apply IGF-I to old muscle after hindlimb immobilization in order to further identify those genes that failed to respond in old muscles, but had responded in young muscles. Specific aim 3 will begin to characterize for those differentially expressed ESTs between young and old muscles after ending immobilization in Specific aims 1 and 2. To support data analysis in Specific aims 1 and 2, Specific aim 4 will develop a computer-based, automated system for analysis of microarray data, data warehousing system for high capacity data storage, and tools for querying microarray data across experiments. Identifying the inappropriately expressed mRNAs associated with failed muscle regrowth of old muscles will permit a more scientifically-based growth factor rescue of old atrophied muscle.

一个常见的临床问题是，在许多疗养院中，存在移动的和功能正常的老年人，他们在由于疾病或受伤而经历一个或多个不动期后，不能恢复移动性。即使经过广泛的康复治疗，这些人中的许多人也无法恢复到受伤前的功能水平。动物模型模仿了人类的这种状况。经历10天后肢固定期的年轻和老年大鼠都表现出废用性萎缩，但只有年轻大鼠的骨骼肌成功地从这种废用性萎缩中再生，因为老年肌肉在恢复77天后没有再生。假设2如下：“在200种mRNA中，有10种对应于生长因子、生长因子受体或受体后信号传导，这些mRNA存在于所用的微阵列上，在老年骨骼肌在重新加载期间无法从固定诱导的萎缩中拯救自己的过程中，年轻大鼠和老年大鼠之间会有所不同。具体目标1将确定一个池的mRNA与失败的老骨骼肌拯救自己从固定诱导的萎缩在重新加载。另一个观察结果是，短期IGF-I应用将挽救废用性萎缩后旧肌肉再生的失败。然而，这种效果只是短暂的，因为持续的IGF-I应用于旧肌肉消耗剩余的卫星细胞增殖和肌肉废物。因此，必须鉴定所有缺陷生长因子应答。具体目标2将IGF-I应用于后肢固定后的老年肌肉，以进一步鉴定那些在老年肌肉中没有反应，但在年轻肌肉中有反应的基因。具体目标3将开始表征在具体目标1和2中结束固定后年轻和老年肌肉之间差异表达的EST。为了支持具体目标1和2中的数据分析，具体目标4将开发一个基于计算机的自动化系统，用于分析微阵列数据，用于高容量数据存储的数据仓库系统，以及用于跨实验查询微阵列数据的工具。鉴定与老年肌肉再生失败相关的不适当表达的mRNA将允许基于更科学的生长因子拯救老年萎缩肌肉。