The Role of TGF-Beta Signaling in Neural Crest-Mediated Jaw Bone Remodeling

项目总结/摘要 正确建立颌骨长度对进食、呼吸和正常发育至关重要 口腔运动技能颌骨经常显示一系列大小相关的异常，包括 下颌发育不全、下颌后缩、不对称和裂开。颅面缺损的治疗 通常涉及多次手术干预，这是一个漫长的，昂贵的，情感和 物理排水过程。然而，针对高危人群的预防措施 替代.确定潜在的拯救或再生策略取决于对 调节下颚大小的发育过程。下颚，沿着大部分颅面 骨骼，来自神经嵴间充质（NCM），一种短暂的多能细胞 在神经板边缘出现的种群。我们采用了一种独特的体内系统来研究 NCM以及它如何执行分子和组织学程序，以建立大小和 下颌骨的形状了解NCM如何完成如此复杂的任务， 以及确定钳口长度的具体机制仍然未知。我们的出版和 初步结果表明，基质金属蛋白酶（Mmps）的差异调节， Runx 2和转化生长因子-β（TGFβ）以物种特异性方式表达， 造成钳口长度的差异。我们假设NCM差异调节 Mmps、Runx 2和TGFβ以物种特异性方式信号传导，调节骨吸收 以产生钳口长度的变化。为了验证我们的假设，我们联合收割机结合了 鹌鹑和鸭在一个新的嵌合系统的发展计划。鹌鹑有短 而鸭的下颚相对较长，鹌鹑胚胎的发育速度比鸭快得多。 鸭子.鹌鹑和鸭子之间交换NCM提供了一种独特的操纵方式， 供体NCM和邻近宿主组织之间的信号传导，并允许发现NCM- 依赖过程。在目标1中，我们将确定NCM介导 调节下颌大小的MMP。在目标2中，我们将确定颌骨大小是否受到以下因素的影响： NCM介导的Runx 2表达的差异调节。在目标3中，我们将确定 NCM通过TGFβ信号传导介导颌骨长度的程度。我们将采用增益-和 功能丧失策略，以了解骨形成和再吸收的变化， 以及TGFβ如何调节Runx 2和Mmp表达以影响颌骨长度。每个特定 目的是临床相关的，并可能确定分子疗法，可用于 操纵钳口长度。我们相信，我们的研究将为 基于生物学的非手术方法来治疗人类颌骨疾病。

PROJECT SUMMARY/ABSTRACT Proper establishment of jaw length is essential to feeding, breathing, and normal development of oral-motor skills. The jaw often displays an array of size related abnormalities, including mandibular hypoplasia, retrognathia, asymmetry, and clefting. Treatment for craniofacial defects often involves multiple surgical interventions, which is a lengthy, costly, and emotionally and physically draining process. Prevention for at-risk individuals, however, provides a welcome alternative. Identifying potential strategies for rescue or regeneration depends on understanding the developmental processes regulating jaw size. The jaw, along with most of the craniofacial skeleton, derives from the neural crest mesenchyme (NCM), a transient multi-potent cell population that arises at the neural plate border. We employ a unique in vivo system to study the NCM and how it executes molecular and histological programs that establish the size and shape of the jaw skeleton. Understanding how the NCM accomplishes such a complex task, and the specific mechanisms that determine jaw length, remain unknown. Our published and preliminary results suggest that differential regulation of matrix metalloproteinases (Mmps), Runx2, and Transforming Growth Factor-Beta (TGFβ) in a species-specific manner may contribute to differences in jaw length. We hypothesize that the NCM differentially regulates Mmps, Runx2, and TGFβ signaling in a species-specific manner, modulating bone resorption to generate variations in jaw length. To test our hypothesis, we combine the species-specific developmental programs of quail and duck in a novel chimeric system. Quail have short jaws whereas those of duck are relatively long, and quail embryos develop much faster than duck. Exchanging NCM between quail and duck provides a unique way to manipulate signaling between donor NCM and adjacent host tissues, and allows discovery of NCM- dependent processes. In Aim 1, we will determine the extent to which the NCM-mediates Mmps to regulate jaw size. In Aim 2, we will ascertain whether jaw size is affected by differential regulation of NCM-mediated Runx2 expression. In Aim 3, we will determine the extent to which NCM mediates jaw length through TGFβ signaling. We will employ gain- and loss-of-function strategies to understand how changes in bone formation and resorption, and how TGFβ can regulate Runx2 and Mmp expression to affect jaw length. Each Specific Aim is clinically relevant and may identify molecular therapies that can be used to manipulate jaw length. We are confident that our research will provide a foundation for biologically-based, non- surgical methods to treat disorders of the human jaw.