Characterization of myostatin and GDF-11

描述（由申请人提供）：肌生长抑制素（MSTN）和GDF-11是我们最初在筛选与转化生长因子- β (TGF-B)相关的新型生长和分化因子时发现的分泌蛋白。MSTN和GDF-11的预测序列在成熟的c端部分有90%以上的相同，并且这些分子在更大的TGF-B超家族中形成了自己的亚群。我们一直在使用各种体外和体内方法，包括小鼠基因靶向，试图确定MSTN和GDF-11的生物学功能。我们已经证明，缺乏MSTN的小鼠骨骼肌质量显著且广泛增加，这表明MSTN通常作为肌肉生长的负调节因子发挥作用。我们还发现，缺乏GDF-11的小鼠具有广泛的轴向骨架同源转化，这表明GDF-11通常作为轴向模式的全局调节剂。本提案的总体目标是进一步研究这些分子的生物学功能及其活动调节机制。具体目的是：研究MSTN和GDF-11的功能冗余；分析出生后MSTN和GDF-11缺失对骨骼肌质量的影响；进一步表征激活素II型受体在调节MSTN和GDF-11信号传导中的作用；鉴定MSTN和GDF-11受体复合物的其他组分；进一步研究卵泡抑素在调节MSTN和GDF-11活性中的作用；并研究潜伏MSTN被激活的机制。综上所述，这些研究将为这些分子的正常生物学功能提供重要的见解，并可能为调节这些分子的活动提供新的策略，用于肌肉萎缩疾病（如肌肉萎缩症和恶病质）和代谢疾病（如肥胖和II型糖尿病）的人类治疗应用。

DESCRIPTION (provided by applicant): Myostatin (MSTN) and GDF-11 are secreted proteins that we originally identified in a screen for novel growth and differentiation factors related to transforming growth factor-Beta (TGF-B). The predicted sequences of MSTN and GDF-11 are greater than 90% identical in the mature, C-terminal portion of the proteins, and together, these molecules form their own subgroup within the larger TGF-B superfamily. We have been using a variety of in vitro and in vivo approaches, including gene targeting in mice, to attempt to identify the biological functions of MSTN and GDF-11. We have shown that mice lacking MSTN have dramatic and widespread increases in skeletal muscle mass, suggesting that MSTN normally functions as a negative regulator of muscle growth. We have also shown that mice lacking GDF-11 have extensive homeotic transformations of the axial skeleton, suggesting that GDF-11 normally acts as a global regulator of axial patterning. The overall aim of this proposal is to further investigate the biological functions of these molecules and the mechanisms by which their activities are regulated. The specific aims are: to investigate the functional redundancy of MSTN and GDF-11; to analyze the effect of postnatal loss of MSTN and GDF-11 on skeletal muscle mass; to further characterize the role of activin type II receptors in regulating MSTN and GDF-11 signaling; to identify other components of the MSTN and GDF-11 receptor complex; to further investigate the role of follistatin in regulating MSTN and GDF-11 activity; and to investigate the mechanism by which latent MSTN is activated. Taken together, these studies will provide important insights into the normal biological functions of these molecules and may suggest new strategies for modulating the activities of these molecules for human therapeutic applications in muscle wasting diseases, such as muscular dystrophy and cachexia, andmetabolic diseases, such as obesity and type II diabetes.