Characterization of myostatin and GDF-11

描述（由申请人提供）：转化生长因子-？ (TGF-?) 超家族包含一大群分泌的信号分子，它们在胚胎发生过程中调节许多不同组织的发育以及维持和调节成年动物中这些组织的功能方面发挥着关键作用。我们的大部分工作集中在两个高度相关的家族成员：肌生长抑制素 (GDF-8) 和 GDF-11，我们最初是根据它们与已知家族成员的同源性克隆的。我们发现，经过基因改造缺乏肌生长抑制素的小鼠，由于肌纤维增生和肥大的结合，全身骨骼肌质量显着增加，这表明肌生长抑制素通常会限制肌肉质量。我们还表明，肌肉生长抑制素的丧失对脂肪和葡萄糖代谢具有显着的有益影响，包括在肥胖和 II 型糖尿病模型中。就 GDF-11 而言，我们发现 Gdf11 敲除小鼠在中轴骨骼模式和肾脏发育方面存在缺陷。其他人已经证明 GDF-11 在神经系统和胰腺的发育中也发挥着重要作用。过去我们的大部分努力都集中在了解消除这些分子功能的发育后果以及识别关键的调控和信号传导成分。我们现在希望集中精力更好地了解它们的产后作用，长期目标是利用它们的活性进行临床应用，特别是在影响骨骼肌和脂肪组织等关键代谢组织的疾病状态下。这一过程的关键是彻底了解这些信号分子的细胞靶标及其作用模式。作为起点，我们将尝试在小鼠中使用遗传策略来识别肌生长抑制素的细胞靶标以及与肌生长抑制素配合调节骨骼肌生长的配体。该项目的具体目标是：确定体内阻断肌纤维中 Smad 功能的效果，并确定卫星细胞在体内介导肌生长抑制素作用中的作用。总而言之，这些研究应该为这些信号分子如何控制骨骼肌生长提供重要的见解。基于对肌肉生长抑制素和相关配体的生物学功能的了解，人们非常关注操纵这一途径来增加肌肉退行性和消耗性疾病患者的肌肉质量和力量，如肌营养不良、肌肉减少症和恶病质，这些疾病常见于癌症、艾滋病和败血症等疾病的患者。此外，我们相信，此类药物的一个同样重要的应用可能是治疗肥胖和二型糖尿病等代谢性疾病，这些疾病不仅在成人中，而且在儿童和青少年中都已达到接近流行的程度。我们相信，这里提出的研究将是阐明这些分子的功能并制定利用其活性进行治疗干预的策略的关键一步。 公共健康相关性：该提案的总体目标是研究肌生长抑制素的细胞靶标，肌生长抑制素是一种信号分子，在调节骨骼肌生长中发挥着关键作用。这些研究可能对预防和治疗多种肌肉消耗性疾病（如肌营养不良症、肌肉减少症和恶病质）以及代谢性疾病（如肥胖和 II 型糖尿病）具有重要意义。

DESCRIPTION (provided by applicant): The transforming growth factor-? (TGF-?) superfamily encompasses a large group of secreted signaling molecules that play critical roles in regulating the development of many different tissues during embryogenesis as well as in maintaining and modulating the functions of these tissues in adult animals. Much of our work has focused on two highly related family members, myostatin (GDF-8) and GDF-11, which we originally cloned on the basis of their homology to known family members. We showed that mice engineered to lack myostatin have dramatic increases in skeletal muscle mass throughout the body resulting from a combination of muscle fiber hyperplasia and hypertrophy, demonstrating that myostatin normally acts to limit muscle mass. We also showed that loss of myostatin has significant beneficial effects on fat and glucose metabolism, including in models of obesity and type II diabetes. In the case of GDF-11, we showed that Gdf11 knockout mice have defects in patterning of the axial skeleton and in kidney development. Others have demonstrated that GDF-11 also plays important roles in the development of the nervous system and pancreas. Much of our effort in the past has focused on understanding the developmental consequences of eliminating the functions of these molecules as well as on identifying key regulatory and signaling components. We would now like to focus our effort on better understanding their postnatal roles, with the long-term goal of exploiting their activities for clinical applications, particularly in disease states affecting key metabolic tissues like skeletal muscle and adipose tissue. Critical to this process will be a thorough understanding of the cellular targets for these signaling molecules as well as their mode of action. As a starting point, we will attempt to use genetic strategies in mice to identify the cellular targets for myostatin and the ligands that cooperate with myostatin to regulate skeletal muscle growth. The Specific Aims of this project are: to determine the effect of blocking Smad function in myofibers in vivo and to determine the role of satellite cells in mediating the effects of myostatin in vivo. Taken together, these studies should provide key insights into how these signaling molecules control skeletal muscle growth. Based on what is known about the biological functions of myostatin and related ligands, there has been an intense focus on manipulating this pathway to increase muscle mass and strength in patients with muscle degenerative and wasting diseases, like muscular dystrophy, sarcopenia, and cachexia, which is often seen in patients with diseases like cancer, AIDS, and sepsis. Moreover, we believe that an equally important application for such agents may turn out to be to treat metabolic diseases, like obesity and type II diabetes, which have reached near epidemic proportions not only in adults but also in children and adolescents. We believe that the studies proposed here will be a crucial step to elucidating the functions of these molecules and developing strategies to exploiting their activities for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The overall aim of this proposal is to investigate the cellular targets for myostatin, which is a signaling molecule that plays a critical role in regulating skeletal muscle growth. These studies could have important implications for the prevention and treatment of a wide range of muscle wasting diseases, like muscular dystrophy, sarcopenia, and cachexia, as well as metabolic diseases, like obesity and type II diabetes.