ROLE OF MYOSTATIN IN CACHEXIA

肌肉生长抑素(GDF-8)是一种新的转化生长因子-β家族成员，对骨骼肌群的正常调节是必不可少的。我们已经证明，缺乏肌肉抑制素的小鼠的肌肉数量是野生型动物的2-3倍，这种肌肉质量的增加是增殖和肥大的组合造成的。我们还表明，在裸鼠体内过度表达肌肉抑制素会导致一种类似于癌症或艾滋病等慢性病患者常出现的恶病质状态的消瘦综合征。本研究的总体目的是确定Smad信号通路在体内介导肌肉生长抑制素效应中的作用，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蛋白活性和/或Smad信号通路在治疗恶病质中的应用的可能性。这项建议的具体目标是：培育和鉴定可操控肌肉生长抑素表达水平的转基因小鼠； 建立和鉴定转基因小鼠，在该转基因小鼠中，显性阴性形式的myostatin或myostatin的前结构域被用来阻断myostatin的表达和/或信号；产生和鉴定转基因小鼠，其中各种转化生长因子-β信号成分的显性阴性形式或抑制物在骨骼肌中特异性表达；确定这些信号成分是否参与小鼠的myostatin信号传递；确定这些信号成分的活动是否对耗竭综合征是必要的。 由IL-6、肿瘤坏死因子-α和某些肿瘤细胞诱导；并确定出生后阻断这些信号成分在骨骼肌中的活性的效果。这些研究将提供有关参与肌肉生长调节的信号分子的关键信息，并将是研究靶向myostatin或Smad通路作为开发新的治疗方法的策略的可能益处的重要第一步。 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.