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。我们已经证明，缺乏肌肉生长抑制素的小鼠的肌肉量是野生型动物的2-3倍，这种肌肉量的增加是由增生和肥大共同造成的。我们还发现，裸鼠体内肌肉生长抑制素的过度表达会诱发一种消瘦综合征，这种综合征类似于人类慢性疾病（如癌症或艾滋病）患者经常出现的恶病质状态。本研究的总体目标是确定Smad信号通路在体内调节肌肉生长抑制素作用中的作用，研究Smad信号通路在调节肌肉生长中的作用，并探讨抑制肌肉生长抑制素活性和/或Smad信号通路在治疗恶病质中的应用可能性。本提案的具体目的是：产生和表征转基因小鼠，其中肌肉生长抑制素的表达水平可以被操纵；来

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.