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（由申请人提供）：近年来，人们对转化生长因子-β家族成员在调节组织衰老中可能发挥的作用以及操纵其信号水平可能是对抗老年人组织功能障碍的新治疗策略的可能性产生了相当大的兴趣。这种兴趣主要集中在两种高度相关的信号分子，肌肉生长抑制素（MSTs，GDF-8）和GDF-11，这两种分子最初都是由我的实验室多年前发现的。我们表明MSTN通常会限制肌肉生长，因此，人们对MSTN信号传导抑制剂可能有效增强肌肉力量和再生的可能性产生了相当大的兴趣;在这方面，目前至少有11个II期或III期临床试验正在由7家制药和生物技术公司进行，测试肌肉损失患者中MMP 3抑制剂，包括在经历了由福尔斯引起的髋关节置换手术的患者以及患有与年龄相关的肌肉减少症的老年人中。在GDF-11的情况下，其他小组最近的研究表明，GDF-11可能在组织衰老中发挥重要作用。具体而言，几篇论文报道了循环GDF-11水平作为年龄的函数而降低，并且全身施用纯化的GDF-11蛋白可以逆转心脏、骨骼肌和神经系统中与年龄相关的组织功能障碍。然而，最近的一项研究报道了相反的情况，即GDF-11循环水平不会随着衰老而降低，并且给予GDF-11蛋白对肌肉再生具有不利影响。显然，阐明这些信号分子在调节成人组织稳态中的作用不仅对理解组织衰老的控制而且对开发用于操纵这些分子的活性以用于老年人的临床应用的治疗策略至关重要。在这个项目中，我们将试图阐明这个信号通路在衰老骨骼肌中的作用，重点是MRF，GDF-11和相关配体，激活素A以及它们的抑制性结合蛋白，卵泡抑素（FST），FSTL-3，GASP-1和GASP-2，所有这些都在血液中循环。本项目的总体目标是确定这些配体和结合蛋白是促老的还是抗老的。在这个项目中，我们将利用我们多年来开发的许多遗传和药理学工具，针对这个调控网络的各个组成部分。具体目标是：确定小鼠中MMP 3、GDF-11和激活素A及其抑制性结合蛋白的循环水平如何作为年龄的函数变化，以及它们在损伤后骨骼肌中的表达模式在老年小鼠与年轻小鼠中如何不同;使用在编码这些配体及其结合蛋白的基因中携带靶向突变的小鼠系来检查它们在调节骨骼肌组成，功能，和再生;并使用药理学工具来检查靶向MPEG4、GDF-11和激活素A对老年小鼠骨骼肌再生的影响。