Characterization of myostatin and GDF-11

肌生长抑制素和 GDF-11 的表征

• 批准号: 6574808
• 负责人: SE-JIN LEE
• 金额: $ 36.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-08 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6574808
• 关键词: CHO cells; cell growth regulation; cell proliferation; follistatin; gene targeting; genotype; high performance liquid chromatography; immunocytochemistry; in situ hybridization; laboratory mouse; molecular cloning; muscle function; myogenesis; myostatin; phenotype; polymerase chain reaction; posttranslational modifications; protein structure function; receptor expression; southern blotting; striated muscles; transforming growth factors; western blottings

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.

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鉴定的分泌蛋白。 MSTN 和 GDF-11 的预测序列在蛋白质的成熟 C 端部分具有超过 90% 的一致性，并且这些分子一起在更大的 TGF-B 超家族中形成自己的亚组。我们一直在使用各种体外和体内方法，包括小鼠基因靶向，试图鉴定 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着而广泛地增加，这表明 MSTN 通常起到肌肉生长的负调节作用。我们还表明，缺乏 GDF-11 的小鼠具有广泛的轴向骨骼同源转化，这表明 GDF-11 通常充当轴向模式的全局调节器。该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性调节机制。具体目的是：研究MSTN和GDF-11的功能冗余；分析产后 MSTN 和 GDF-11 丢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 受体复合物的其他成分；进一步研究卵泡抑素在调节MSTN和GDF-11活性中的作用；并研究潜在MSTN被激活的机制。总而言之，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，并可能提出调节这些分子活性的新策略，用于人类肌肉萎缩疾病（如肌营养不良和恶病质）和代谢疾病（如肥胖和二型糖尿病）的治疗应用。