TGF-beta family members and their binding proteins in aging skeletal muscle

衰老骨骼肌中的 TGF-β 家族成员及其结合蛋白

• 批准号: 9264681
• 负责人: SE-JIN LEE
• 金额: $ 15.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264681
• 关键词: Adult; Age; Aging; Anterior; Binding Proteins; Biotechnology; Blood; C-terminal; Complex; Elderly; Endocrine; Family; Family member; Follistatin; Functional disorder; GDF8 gene; Gene Targeting; Genes; Genetic; Goals; Growth; Health; Heart; Homeostasis; Human; Injury; Laboratories; Ligands; Mus; Muscle; Muscular Atrophy; Mutation; N-terminal; Natural regeneration; Nervous system structure; Operative Surgical Procedures; Pancreas; Paper; Patients; Pattern; Pharmacologic Substance; Phase; Phase III Clinical Trials; Play; Protein Family; Proteins; Reporting; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal Muscle; Skeleton; Testing; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Work; activin A; age related; aged; clinical application; combat; falls; growth-differentiation factor 8; hip replacement arthroplasty; inhibitor/antagonist; interest; mature animal; member; muscle form; muscle regeneration; muscle strength; nephrogenesis; nervous system development; novel therapeutic intervention; paracrine; sarcopenia; therapeutic development; tool

 DESCRIPTION (provided by applicant): In recent years, there has been considerable interest in the possible role that members of the transforming growth factor- family may play in regulating tissue aging and the possibility that manipulating their levels of signaling may be a new therapeutic strategy to combat tissue dysfunction in the elderly. Much of this interest has focused on two highly related signaling molecules, myostatin (MSTN, GDF-8) and GDF-11, both of which were originally identified by my laboratory many years ago. We showed that MSTN normally acts to limit muscle growth, and as a result, there has been considerable interest in the possibility that inhibitors of MSTN signaling might be effective in enhancing muscle strength and regeneration; in this respect, there are currently at least 11 phase II or phase III clinical trial being conducted by 7 pharmaceutical and biotechnology companies testing MSTN inhibitors in patients with muscle loss, including in patients who have undergone hip replacement surgery resulting from falls as well as in the elderly with age-related sarcopenia. In the case of GDF-11, recent studies by other groups have suggested that GDF-11 may play an important role in tissue aging. Specifically, several papers reported that circulating GDF-11 levels decrease as a function of age and that systemic administration of purified GDF-11 protein can reverse age-related tissue dysfunction in the heart, skeletal muscle, and nervous system. A very recent study, however, reported the opposite, namely, that GDF-11 circulating levels do not decrease with aging and that administering GDF-11 protein has a detrimental effect on muscle regeneration. Clearly, elucidating the roles of these signaling molecules in regulating adult tissue homeostasis will be critical not only to understanding the control of tissue aging but also to the development of therapeutic strategies for manipulating the activities of these molecules for clinical applications in the elderly. In this project, we will attempt to elucidate the roles o this signaling pathway in aging skeletal muscle by focusing on MSTN, GDF-11, and the related ligand, activin A as well as their inhibitory binding proteins, follistatin (FST), FSTL-3, GASP-1, and GASP-2, all of which circulate in the blood. The overall goal of this project is to determine whether these ligands and binding proteins are pro-geronic or anti-geronic. For this project, we will take advantage of the many genetic and pharmacological tools that we have developed over many years targeting the various components of this regulatory network. The Specific Aims are: to determine how circulating levels of MSTN, GDF-11, and activin A and their inhibitory binding proteins change as a function of age in mice and how their expression patterns in skeletal muscle following injury differ in aged versus young mice; to use mouse lines carrying targeted mutations in genes encoding these ligands and their binding proteins to examine their roles in regulating skeletal muscle composition, function, and regeneration in aged mice; and to use pharmacological tools to examine the effect of targeting MSTN, GDF-11, and activin A on skeletal muscle regeneration in aged mice.

 描述（由适用提供）：近年来，转化生长因子-家族的成员可能在控制组织衰老方面发挥的可能作用引起了极大的兴趣，并且操纵其信号传导水平可能是一种新的理论策略，可以打击旧的组织功能障碍。这种兴趣的大部分集中在两个高度相关的信号分子肌抑制素（MSTN，GDF-8）和GDF-11上，这两者最初是由我的实验室确定的。我们表明，MSTN通常会限制肌肉生长，因此，MSTN信号抑制剂可能有效增强肌肉强度和再生有效的可能性。在这方面，目前至少有11次II期或III期临床试验由7家药物和生物技术公司进行测试肌肉损失患者的MSTN抑制剂，包括在跌倒以及与年龄相关的肌肉细胞的患者中进行的髋关节置换手术。就GDF-11而言，其他小组的最新研究表明，GDF-11可能在组织衰老中起重要作用。具体而言，几篇论文报告说，循环GDF-11水平随着年龄的函数而降低，并且全身纯化的GDF-11蛋白可以在心脏，骨骼肌和神经系统中逆转与年龄相关的组织功能障碍。然而，一项最近的研究报告了相反的情况，即GDF-11循环水平不会随老化而降低，而给予GDF-11蛋白的一项循环水平对肌肉再生有害。显然，阐明这些信号分子在衡量成年组织稳态中的作用不仅至关重要，这不仅要了解组织衰老的控制，而且对于制定了处理这些分子在较老的临床应用中的活性的理论策略的发展。在这个项目中，我们将尝试通过关注MSTN，GDF-11和相关的配体，Activin a以及其抑制性结合蛋白Follistatin（FSTL-3），FSTL-3，GASP-1和GASP-2和GASP-2，所有循环中的蛋白质，均应阐明这种信号传导途径。该项目的总体目标是确定这些配体和结合蛋白是促源性还是抗蛋白质。对于这个项目，我们将利用我们针对该监管网络各种组成部分的许多遗传和药品工具的优势。具体目的是：确定MSTN，GDF-11和激活素A的循环水平以及它们的抑制结合蛋白如何随着小鼠的年龄的函数而变化，以及它们在衰老小鼠损伤差异后骨骼肌中的表达模式如何变化；在编码这些配体及其结合蛋白的基因中使用携带靶向突变的小鼠系，以检查其在老年小鼠中恢复骨骼肌组成，功能和再生中的作用；并使用药物工具来检查靶向MSTN，GDF-11和激活素A对老年小鼠骨骼肌再生的影响。