Characterization of myostatin and GDF-11

肌生长抑制素和 GDF-11 的表征

• 批准号: 7781924
• 负责人: SE-JIN LEE
• 金额: $ 38.68万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781924
• 关键词: Acquired Immunodeficiency Syndrome; Adipose tissue; Adolescent; Adult; Affect; Anterior; Biological Process; Cachexia; Child; Clinical; Defect; Development; Differentiation and Growth; Disease; Embryonic Development; Engineering; Epidemic; Family member; Fatty acid glycerol esters; Gene Targeting; Genetic; Goals; Hyperplasia; Hypertrophy; Individual; Knockout Mice; Laboratories; Ligands; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Methods; Modeling; Mus; Muscle; Muscle Fibers; Muscular Dystrophies; Nervous system structure; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Play; Prevention; Process; Protein Family; Role; Sepsis; Signal Transduction; Signaling Molecule; Skeletal Muscle; Skeleton; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factors; Wasting Syndrome; Work; base; cellular targeting; clinical application; combat; glucose metabolism; growth-differentiation factor 8; human GDF8 protein; human disease; in vivo; insight; mature animal; member; muscle form; myostatin; nephrogenesis; nervous system development; postnatal; public health relevance; research study; sarcopenia; satellite cell; skeletal muscle growth

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.

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信号分子，在胚胎发生过程中调节许多不同组织的发育，并在成年动物中维持和调节这些组织的功能中发挥关键作用。我们的大部分工作集中在两个高度相关的家族成员，肌肉生长抑制素（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，缺乏肌肉生长抑制素的小鼠由于肌纤维增生和肥大的结合，全身骨骼肌质量急剧增加，这表明肌肉生长抑制素通常起限制肌肉质量的作用。我们还发现，在肥胖和II型糖尿病模型中，肌生长抑制素的缺失对脂肪和葡萄糖代谢有显著的有益影响。在GDF-11的情况下，我们发现Gdf11敲除小鼠在轴向骨架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起着重要作用。过去，我们的大部分工作都集中在理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。我们现在想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动用于临床应用，特别是在影响关键代谢组织（如骨骼肌和脂肪组织）的疾病状态中。这一过程的关键将是彻底了解这些信号分子的细胞靶标以及它们的作用方式。作为一个起点，我们将尝试在小鼠中使用遗传策略来确定肌肉生长抑制素的细胞靶点以及与肌肉生长抑制素合作调节骨骼肌生长的配体。该项目的具体目的是：确定体内阻断Smad功能在肌纤维中的作用，并确定卫星细胞在体内介导肌肉生长抑制素作用中的作用。综上所述，这些研究应该为这些信号分子如何控制骨骼肌生长提供关键的见解。基于已知的肌肉生长抑制素和相关配体的生物学功能，人们一直高度关注操纵这一途径，以增加肌肉退行性和消耗性疾病（如肌肉萎缩症、肌肉减少症和恶病质）患者的肌肉质量和力量，这些疾病常见于癌症、艾滋病和败血症等疾病患者。此外，我们认为，这些药物的一个同样重要的应用可能是治疗代谢性疾病，如肥胖和II型糖尿病，这些疾病不仅在成人中，而且在儿童和青少年中都已达到近乎流行病的程度。我们相信，这里提出的研究将是阐明这些分子的功能和开发利用其活动进行治疗干预的策略的关键一步。