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

基本信息

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
项目类别：
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

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

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项目摘要

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.

该项目的重点是调查肌抑素/GDF-11/激活素分支的作用在控制骨骼和密度。这种信号通路在调节骨稳态中起着的重要作用是由针对这组配体的受体的药理和遗传研究记录。工作来自包括我们在内的几个小组，都表明，两种固体形式的全身性给药 Acivin 2型受体ACVR2和ACVR2B能够诱导骨密度显着增加。经过从遗传上靶向成骨细胞中的这些受体，我们表明至少有一部分这种效应是由于抑制直接信号对骨头。但是，令人惊讶的是，我们最近表明，针对1型成骨细胞中的受体ALK4和ALK5导致更大的影响，导致骨骼增加质量和密度约为10倍。这些发现揭示了骨骼的非凡能力通常会受到此监管系统检查的应计，并提出增加的潜力通过靶向此信号通路，骨骼质量和密度大大比以前所欣赏的要大得多。作为制定最有效策略来利用这一途径的潜力的起点对于骨骼应用，我们将阐明在此调节中起关键作用的细胞外成分骨头网络。在特定目标1中，我们将研究该组已知的抑制性结合蛋白的作用配体在确定骨结构中的。在最近的研究中，我们对一种结合蛋白，即follistatin（FST），使用一般靶向的小鼠线，其中表达水平 FST的上调或下调。在这里，我们将研究其他三个已知绑定的作用蛋白质，FSTL-3，GASP-1和GASP-2，使用我们同时携带的靶向小鼠系这些组件中的每个组件的删除和floxErxEreles。在特定目标2中，我们将研究 TGF-ß超家族的该亚组中的特定配体在调节骨骼结构中。在我们最近的研究中，我们表明仅针对两个配体，即肌抑制素和激活素A，导致大幅增加在骨质量和密度中，这些增加显着的明显比我们在靶向其1型受体时观察到的10倍。在这里，我们将使用遗传方法检查配体在TGF-ß超家族的该亚组中的更广泛的配体在调节骨骼中的作用结构。该项目的总体目标是阐明特定的细胞外信号传导组件该在将骨骼体内平衡的定位在开发最有效的长期目标方面起着关键作用针对这种信号通路以治疗骨质流失的策略。