Characterization of Myostatin and GDF-11

肌肉生长抑制素和 GDF-11 的表征

• 批准号: 8513775
• 负责人: SE-JIN LEE
• 金额: $ 33.55万
• 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/8513775
• 关键词: Acquired Immunodeficiency Syndrome; Adipose tissue; Adolescent; Adult; Affect; Anterior; Biological Process; Cachexia; Child; Clinical; Defect; Degenerative Disorder; Development; Differentiation and Growth; Disease; Embryonic Development; Engineering; Epidemic; Family member; 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; lipid metabolism; mature animal; member; muscle form; muscle strength; 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.

性状（申请人提供）：转化生长因子-？(TGF-?)超家族包括一大组分泌的信号分子，其在胚胎发生期间调节许多不同组织的发育以及在成年动物中维持和调节这些组织的功能中起关键作用。我们的大部分工作都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，我们最初克隆的基础上，他们的同源性已知的家庭成员。我们发现，由于肌纤维增生和肥大的结合，经工程改造缺乏肌生长抑制素的小鼠全身骨骼肌质量显著增加，表明肌生长抑制素通常起到限制肌肉质量的作用。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著的有益作用，包括在肥胖和II型糖尿病模型中。在GDF-11的情况下，我们发现Gdf 11基因敲除小鼠在中轴骨骼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。我们过去的大部分努力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组件上。我们现在想集中精力更好地了解它们在出生后的作用，长期目标是将它们的活性用于临床应用，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中。这一过程的关键将是彻底了解这些信号分子的细胞靶点及其作用模式。作为一个起点，我们将尝试在小鼠中使用遗传策略来识别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。本项目的具体目的是：确定在体内阻断肌纤维中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关键见解。基于对肌生长抑制素和相关配体的生物学功能的了解，人们一直高度关注操纵这一途径以增加患有肌肉退行性和消耗性疾病的患者的肌肉质量和力量，如肌营养不良症，肌肉减少症和恶病质，这通常见于癌症，艾滋病和败血症等疾病的患者。此外，我们认为，这类药物的一个同样重要的应用可能是治疗代谢性疾病，如肥胖症和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已接近流行病的程度。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性进行治疗干预的策略的关键一步。