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: 9420283
• 负责人: SE-JIN LEE
• 金额: $ 50.05万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9420283
• 关键词: Adult; Age; Aging; Anterior; Binding Proteins; Biological; Biotechnology; Blood; C-terminal; Complex; Drosophila pros protein; Elderly; Endocrine; Family; Family member; Follistatin; Functional disorder; GDF8 gene; Gene Targeting; Genes; Genetic; Goals; Growth; Heart; Homeostasis; Human; Injury; Laboratories; Ligands; Mus; Muscle; Muscular Atrophy; Mutation; N-terminal; Nervous system structure; Operative Surgical Procedures; Pancreas; Paper; Parabiosis; Patients; Pattern; Pharmacologic Substance; Pharmacology; 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; muscular system; nephrogenesis; nervous system development; novel therapeutic intervention; paracrine; sarcopenia; therapeutic development; tool

PROJECT SUMMARY In recent years, there has been considerable interest in the possible role that members of the transforming growth factor-ß 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 trials 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. Other studies, 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 of 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 the roles of these proteins in regulating skeletal muscle and other tissues in aged mice; and to use genetic and pharmacological approaches in conjunction with parabiosis studies to examine effects of targeting these ligands and binding proteins on skeletal muscle regeneration in aged mice.

项目总结 近年来，人们对该委员会成员可能扮演的角色非常感兴趣 转化生长因子家族可能在调节组织衰老中发挥作用 它们的信号水平可能是对抗老年人组织功能障碍的一种新的治疗策略。大部分 人们的兴趣主要集中在两个高度相关的信号分子，myostatin(MSTN，GDF-8)和GDF-11， 这两种病毒最初都是我的实验室在很多年前发现的。我们显示MSTN正常 限制肌肉生长，因此，人们对这种可能性产生了相当大的兴趣 MSTN信号的抑制剂可能在增强肌肉力量和再生方面有效；在这方面， 目前至少有11项II期或III期临床试验正在进行，由7家制药公司和 生物技术公司在肌肉丧失患者中测试MSTN抑制剂，包括在 接受了跌倒导致的髋关节置换手术，以及患有年龄相关性石棺减少的老年人。在……里面 以GDF-11为例，其他组织最近的研究表明，GDF-11可能在 组织老化。具体地说，几篇论文报道了循环中的GDF-11水平随着年龄的增加而下降 全身应用纯化的GDF-11蛋白可以逆转衰老相关的组织功能障碍。 心脏、骨骼肌和神经系统。然而，其他研究报告了相反的情况，即GDF- 11循环水平不会随着年龄的增长而降低，服用GDF-11蛋白会产生有害影响 肌肉再生。显然，阐明这些信号分子在调节成人组织中的作用 动态平衡不仅对理解组织衰老的控制至关重要，而且对 控制这些分子活性的治疗策略，用于老年人的临床应用。 在这个项目中，我们将试图通过以下方式阐明这一信号通路在骨骼肌衰老中的作用 重点关注MSTN，GDF-11及其相关配体激活素A及其抑制结合蛋白， 卵泡抑素(FST)、FSTL-3、GAP-1和GAP-2，所有这些都在血液中循环。这个项目的总体目标是 项目是确定这些配体和结合蛋白是亲老年性的还是抗老年性的。为了这个 项目，我们将利用我们多年来开发的许多遗传和药理学工具 多年来，针对这一监管网络的各个组成部分。具体目标是：确定 循环中MSTN、GDF-11和激活素A及其抑制结合蛋白的水平如何随着 AGE在小鼠中的作用及其在损伤后骨骼肌中的表达模式 对照幼鼠；使用携带这些配体和它们的编码基因的靶向突变的小鼠品系 结合蛋白研究这些蛋白在调节老年人骨骼肌和其他组织中的作用 利用遗传学和药理学方法，结合异种共生研究，检查 靶向这些配体和结合蛋白对老年小鼠骨骼肌再生的影响。