Extracellular regulation of bone mass by transforming growth factor-ß-related ligands and their binding proteins

通过转化生长因子相关配体及其结合蛋白对骨量进行细胞外调节

• 批准号: 10537833
• 负责人: EMILY L GERMAIN-LEE
• 金额: $ 63.89万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537833
• 关键词: ACVR2 gene; ACVR2B gene; Activin A type II receptor; Activins; Acute; Affect; Binding Proteins; Bone Density; Bone Diseases; Bone structure; Chronic; Complex; Development; Differentiation and Growth; Family member; Follistatin; GDF8 gene; Genetic; Genetic study; Goals; Growth; Health; Homeostasis; Individual; Ligands; LoxP-flanked allele; Molecular; Mus; Muscle; Names; Osteoblasts; Pathway interactions; Patients; Pharmacology; Pharmacology Study; Physiological; Play; Regulation; Regulatory Pathway; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal Muscle; Subgroup; System; TGF-beta type I receptor; Tissues; Transforming Growth Factors; Work; activin A; bone; bone loss; bone mass; clinical application; extracellular; genetic approach; interest; morphogens; muscle form; novel therapeutic intervention; preservation; prevent; receptor; skeletal muscle growth; stem; tool; virtual

The focus of this project will be to investigate the role of the myostatin/GDF-11/activin branch of the transforming growth factor-ß (TGF-ß) superfamily of secreted signaling molecules in regulating bone mass and density. The important role that this signaling pathway plays in regulating bone homeostasis has been documented by both pharmacologic and genetic studies targeting receptors for this group of ligands. Work from several groups, including ours, has shown that systemic administration of soluble forms of either of the activin type 2 receptors, ACVR2 and ACVR2B, is capable of inducing significant increases in bone density. By genetically targeting these receptors in osteoblasts, we showed that at least part of this effect is due to inhibition of direct signaling to bone. Strikingly, however, we very recently showed that targeting the type 1 receptors, ALK4 and ALK5, in osteoblasts led to much more substantial effects, resulting in increases in bone mass and density by approximately 10-fold. These findings revealed the extraordinary capacity for bone accrual that is normally kept in check by this regulatory system and suggest that the potential for increasing bone mass and density by targeting this signaling pathway is substantially greater than previously appreciated. As a starting point for developing the most effective strategies to harness the potential of targeting this pathway for bone applications, we will elucidate the extracellular components that play key roles in this regulatory network in bone. In Specific Aim 1, we will examine the roles of known inhibitory binding proteins for this group of ligands in regulating bone structure. In our recent study, we carried out an extensive analysis of the role of one binding protein, namely follistatin (FST), using genetically-targeted mouse lines in which expression levels of FST were either up- or down-regulated. Here, we will examine the roles of the three other known binding proteins, FSTL-3, GASP-1, and GASP-2, utilizing targeted mouse lines that we have generated carrying both deletion and floxed alleles for each of these components. In Specific Aim 2, we will examine the roles of specific ligands in this subgroup of the TGF-ß superfamily in regulating bone structure. In our recent study, we showed that targeting two ligands simultaneously, namely myostatin and activin A, led to substantial increases in bone mass and density but that these increases were significantly less pronounced than the approximately 10-fold effects that we observed upon targeting their type 1 receptors. Here, we will use genetic approaches to examine the roles of a wider spectrum of ligands in this subgroup of the TGF-ß superfamily in regulating bone structure. The overall goal of this project will be to elucidate the specific extracellular signaling components that play key roles in regulating bone homeostasis with the long-term goal of developing the most effective strategies to target this signaling pathway to treat bone loss.

本项目的重点将是研究肌肉生长抑制素/GDF-11/激活素分支在肿瘤细胞中的作用。 转化生长因子-β（TGF-β）超家族的分泌信号分子在调节骨量和 密度的该信号通路在调节骨稳态中的重要作用已经被证实。 药理学和遗传学研究都证明了这组配体的靶向受体。工作 包括我们在内的几个研究小组的研究表明， 激活素2型受体ACVR 2和ACVR 2B能够诱导骨密度的显著增加。通过 在成骨细胞中遗传靶向这些受体，我们表明，这种效应至少部分是由于 抑制对骨的直接信号传导。然而，引人注目的是，我们最近发现，针对1型糖尿病， 受体，ALK 4和ALK 5，在成骨细胞导致更实质性的影响，导致骨增加， 质量和密度增加了大约10倍这些发现揭示了骨骼的非凡能力 这一监管制度通常会控制应计费用，并表明增加的潜力 通过靶向该信号传导途径的骨质量和骨密度显著大于先前认识到的。 作为制定最有效战略的起点，利用针对这一途径的潜力 对于骨的应用，我们将阐明细胞外组分在这种调节中起关键作用， 网络在骨在具体目标1中，我们将研究已知的抑制性结合蛋白对这一组的作用 配体在调节骨骼结构中的作用。在我们最近的研究中，我们进行了广泛的分析， 一种结合蛋白，即卵泡抑素（FST），使用基因靶向小鼠系， FST的表达上调或下调。在这里，我们将研究其他三种已知绑定的作用， 蛋白质，FSTL-3，GASP-1和GASP-2，利用我们已经产生的携带这两种蛋白质的靶向小鼠系， 缺失和floxed等位基因。在具体目标2中，我们将研究 TGF-β超家族的这个亚组中的特异性配体调节骨结构。在最近的研究中，我们 同时靶向两种配体，即肌肉生长抑制素和激活素A， 在骨量和密度，但这些增加显着不太明显， 10-我们在靶向它们的1型受体时观察到的倍数效应。在这里，我们将使用遗传方法， 研究TGF-β超家族中更广泛的配体在调节骨形成中的作用 结构本项目的总体目标将是阐明特定的细胞外信号成分 在调节骨稳态方面发挥关键作用，长期目标是开发最有效的 针对这一信号通路治疗骨质流失的策略。