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

项目摘要/摘要 适当的下巴长度对进食、呼吸和正常发育是必不可少的 口腔运动技能。颌骨通常显示一系列与大小相关的异常，包括 下颌发育不全、下颌后突、不对称和裂开。颅面骨缺损的治疗 通常涉及多个手术干预，这是一个冗长、昂贵和情绪和 体力消耗过程。然而，对高危人群的预防提供了一个可喜的机会。 另类选择。确定救援或再生的潜在战略取决于对 调节颌骨大小的发育过程。下巴，还有大部分的头面部 骨骼，起源于神经脊间充质(NCM)，一种瞬时的多能细胞 出现在神经板边界的种群。我们使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来确定大小和 颌骨的形状。了解NCM如何完成如此复杂的任务， 而决定颌骨长度的具体机制仍不清楚。我们出版的和 初步结果表明，基质金属蛋白酶(MMPs)、 Runx2和转化生长因子-β(转化生长因子β)以物种特异性的方式可以 造成颌骨长度差异的原因之一。我们假设NCM对不同的 MMPs、Runx2和转化生长因子β以物种特异性的方式信号转导，调节骨吸收 以产生颌骨长度的变化。为了检验我们的假设，我们结合了物种特有的 一个新的嵌合系统中的鹌鹑和鸭子的发育程序。鹌鹑有短 鸭子的下巴相对较长，而鹌鹑胚胎的发育速度要快于 鸭子。在鹌鹑和鸭子之间交换NCM提供了一种独特的操作方式 供体NCM和邻近宿主组织之间的信号转导，并允许发现NCM- 从属进程。在目标1中，我们将确定NCM-调解的程度 MMPs调节颌骨大小。在目标2中，我们将确定颌骨大小是否受 NCM介导的Runx2表达的差异调控。在目标3中，我们将确定 NCM通过转化生长因子β信号调节颌长的程度。我们将采用Gain-And 功能丧失策略，以了解骨形成和吸收的变化， 以及转化生长因子β如何调节Runx2和MMP2的表达从而影响颌长。每个特定的 AIM在临床上是相关的，并可能确定可用于 调整下巴长度。我们相信，我们的研究将为 以生物为基础的、非手术的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.