Characterization of Myostatin and GDF-11

肌肉生长抑制素和 GDF-11 的表征

• 批准号: 9118610
• 负责人: SE-JIN LEE
• 金额: $ 39.55万
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118610
• 关键词: Adult; Age; Aging; Anterior; Binding Proteins; Biochemical; Biological Process; Biotechnology; Clinical Trials; Code; Development; Differentiation and Growth; Disease; Elderly; Embryonic Development; Family member; Fiber; Functional disorder; GDF11 gene; GDF8 gene; Gene Targeting; Genes; Genetic; Goals; Growth; Heart; Homeostasis; Hypertrophy; In Vitro; Knock-in; Laboratories; Ligands; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Myocardium; Nervous system structure; Pancreas; Paper; Patients; Pattern; Pharmacologic Substance; Phase; Phase III Clinical Trials; Play; Proteins; Regulation; Reporting; Research; Role; Signal Transduction; Signaling Molecule; Skeletal Muscle; Skeleton; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factors; Work; age related; aged; base; biochemical tools; clinical application; combat; growth-differentiation factor 8; in vivo; inhibitor/antagonist; insight; interest; mature animal; member; muscle form; muscle regeneration; muscle strength; nephrogenesis; nervous system development; postnatal; public health relevance; receptor; research study

 DESCRIPTION (provided by applicant): The main focus of our research has been to understand the biological functions of two highly related signaling molecules, myostatin (MSTN, GDF-8) and GDF-11, which we discovered in a screen for new transforming growth factor-ß family members. We showed that mice lacking MSTN have dramatic increases in skeletal muscle mass throughout the body, and we and others showed that systemic administration of MSTN inhibitors to mice can promote muscle growth, showing that MSTN acts to limit muscle growth postnatally. Hence, there is extensive interest in targeting MSTN to enhance muscle strength and regeneration, and at least 7 biotechnology and pharmaceutical companies are in phase II/III clinical trials testing myostatin inhibitors in a wide range of disease settings. We showed that GDF-11 plays an important role in axial patterning and in kidney development, and other groups subsequently showed that GDF-11 also regulates the development of the nervous system and pancreas. Gdf11 is expressed widely in adult tissues, and recent studies have suggested that GDF-11 may play an important role in aging. Specifically, circulating GDF-11 levels were reported to decrease with age, and administration of GDF-11 protein to aged mice was reported to reverse age-related tissue dysfunction in the heart, skeletal muscle, and nervous system. Some of these findings have since been challenged by a paper reporting that GDF-11 levels increase with aging and that GDF-11 has a detrimental effect on skeletal muscle regeneration. These findings have raised new questions regarding the roles of MSTN and GDF-11 in adult animals as well as the potential strategies for manipulating the activities of these molecules for clinical applications. A major question in this regard is whether the distinct functions of MSTN and GDF-11 reflect the inherent biochemical differences between these highly related molecules or whether their distinct functions simply reflect their differing pattern of expression. The overall goal of this project is to understand the basis for the distinct functios of these molecules. This project is a continuation of our long-standing effort to understand the mechanisms underlying the regulation and signaling of MSTN and GDF-11 and will utilize the many genetic and biochemical tools that we have developed over many years to target the various components of this regulatory network. The Specific Aims are: to compare the activities of MSTN and GDF-11 in vitro with respect to the roles of known signaling components, including inhibitory binding proteins and receptors; to examine the roles of these binding proteins and receptors in regulating skeletal and cardiac muscle growth and function and skeletal muscle regeneration in vivo; and to carry out gene knock-in experiments in mice in which the MSTN coding sequence is replaced with GDF-11 (and vice versa). The results of these experiments should provide key insights into the mechanistic basis underlying the distinct biological functions that MSTN and GDF-11 carry out in vivo. We believe that these studies will be crucial for developing strategies to exploit the activities of these molecules for therapeutic intervention.

 描述（由适用提供）：我们研究的主要重点是了解两个高度相关的信号分子的生物学功能，即肌生抑素（MSTN，GDF-8）和GDF-111，我们在新的转化生长因子-β家族成员的屏幕中发现了这两个高度相关的信号。我们表明，缺乏MSTN的小鼠在整个体内的骨骼肌质量急剧增加，而我们和其他人则表明，全身对MSTN抑制剂对小鼠的施用可以促进肌肉的生长，表明MSTN的行为可在产后限制肌肉生长。因此，人们对靶向MSTN具有广泛的兴趣，以增强肌肉力量和再生，并且至少有7家生物技术和制药公司正在II/III期临床试验中测试在广泛的疾病环境中肌生抑制蛋白抑制剂。我们表明，GDF-11在轴向图案和肾脏发育中起着重要作用，其他组随后表明GDF-11还调节了神经系统和胰腺的发育。 GDF11在成人组织中广泛表达，最近的研究表明，GDF-11可能在衰老中起重要作用。具体而言，据报道，循环GDF-11水平随着年龄的增长而降低，据报道，GDF-11蛋白在老年小鼠中施用会逆转与年龄相关的组织功能障碍，心脏，骨骼肌和神经系统。此后，其中一些发现受到论文报告的挑战，即GDF-11水平随衰老而增加，而GDF-11对骨骼肌再生有害。这些发现提出了有关MSTN和GDF-11在成年动物中的作用以及操纵这些分子在临床应用中的活性的潜在策略的新问题。在这方面的一个主要问题是，MSTN和GDF-11的不同功能是否反映了这些高度相关分子之间固有的生化差异，或者它们的独特功能是否仅仅反映了它们的不同表达方式。该项目的总体目标是了解这些分子不同功能的基础。该项目是我们长期以来一直努力了解MSTN和GDF-11的调节和信号传导的机制的延续，并将利用我们多年来开发的许多遗传和生化工具来针对该监管网络的各个组成部分。具体目的是：在体外比较MSTN和GDF-11的活性，相对于已知信号成分的作用，包括抑制性结合蛋白和受体；检查这些结合蛋白和受体在确定体内骨骼肌和心脏肌肉生长以及功能以及骨骼肌再生中的作用；并在小鼠中进行基因敲入实验，其中MSTN编码序列被GDF-11取代（反之亦然）。这些实验的结果应提供对不同生物学功能的机械基础的关键见解 MSTN和GDF-11在体内进行。我们认为，这些研究对于制定利用这些分子的活动进行治疗干预的策略至关重要。