ROLE OF MYOSTATIN IN CACHEXIA

肌生长抑制素（GDF-8）是一种新的TGF-β家族成员，对骨骼肌质量的适当调节至关重要。我们已经表明，缺乏肌生长抑制素的小鼠具有野生型动物中存在的肌肉量的2-3倍，并且这种肌肉质量的增加是由增生和肥大的组合引起的。我们还发现，肌生长抑制素在裸鼠中的过度表达诱导了一种消耗综合征，类似于患有慢性疾病如癌症或艾滋病的人类患者中常见的恶病质状态。本提案的总体目标是确定Smad信号通路在体内介导肌生长抑制素的作用，研究Smad通路在调节肌肉生长中的作用，并探索抑制肌生长抑制素活性和/或Smad信号通路可能应用于恶病质治疗的可能性。该提议的具体目的是：产生和表征转基因小鼠，其中肌生长抑制素的表达水平可以被操纵; 产生和表征转基因小鼠，其中肌生长抑制素的显性负性形式或肌生长抑制素的前结构域用于阻断肌生长抑制素表达和/或信号传导;产生和表征转基因小鼠，其中各种TGF-β信号传导组分的显性负性形式或抑制剂在骨骼肌中特异性表达;确定这些信号传导组分是否参与小鼠中的肌生长抑制素信号传导;以确定这些信号成分的活性是否是消耗综合征所必需的 诱导的IL-6，TNF-α，和某些肿瘤细胞;并确定在骨骼肌中这些信号传导成分的活性的出生后阻断的效果。这些研究将提供关于参与肌肉生长调节的信号分子的关键信息，并且将是研究靶向肌生长抑制素或Smad通路作为开发用于治疗肌生长抑制素的新疗法的策略的可能益处的重要的第一步。 恶病质

Myostatin (GDF-8) is a new TGF-beta family member that is essential for proper regulation of skeletal muscle mass. We have shown that mice lacking myostatin have 2-3 times the amount of muscle present in wild type animals and that this increase in muscle mass results from a combination of hyperplasia and hypertrophy. We have also shown that overexpression of myostatin in nude mice induces a wasting syndrome that resembles the cachectic state often seen in human patients with chronic diseases such as cancer or AIDS. The overall aims of this proposal are to determine the role of the Smad signaling pathway in mediating the effects of myostatin in vivo, to investigate the role of the Smad pathway in regulating muscle growth, and to explore the possibility that inhibition of myostatin activity and/or Smad signaling may have applications in the treatment of cachexia. The specific aims of this proposal are: to generate and characterize transgenic mice in which the expression levels of myostatin can be manipulated; to generate and characterize transgenic mice in which a dominant negative form of myostatin or the pro- domain of myostatin is used to block myostatin expression and/or signaling; to generate and characterize transgenic mice in which either dominant negative forms or inhibitors of various TGF-beta signaling components are expressed specifically in skeletal muscle; to determine whether these signaling components are involved in myostatin signaling in mice; to determine whether the activities of these signaling components are essential for the wasting syndrome induced by IL-6, TNF-alpha, and certain tumor cells; and to determine the effects of blocking the activities of these signaling components postnatally in skeletal muscle. These studies will provide key information regarding the signaling molecules involved in the regulation of muscle growth and will be an important first step in investigating the possible benefits of targeting myostatin or the Smad pathway as a strategy for developing novel therapies for the treatment of cachexia.