Regional differences in neural crest and mesodermal derived calvarial bone healin

描述(申请人提供)：我们提出，个别哺乳动物头盖骨独特的胚胎起源影响其成骨能力的差异。这一建议的核心假设是，颅骨成骨细胞胚胎来源的不同会影响其胚胎和出生后的成骨能力和骨骼再生能力。前颅骨中成对的顶额骨来自神经脊，位于后方的成对顶骨来自轴旁中胚层。我们初步观察到，与顶骨相比，额骨在体外和体内都具有更好的成骨能力。我们的建议旨在验证成骨潜能的这种差异，并阐明成纤维细胞生长因子(成纤维细胞生长因子)信号在这种差异中的作用。这样的理解对于克服目前颅骨缺陷治疗方面的挑战至关重要。年龄超过一岁的人无法修复颅骨缺陷，这给我们的医疗保健系统带来了巨大的负担。目前使用自体移植物、同种异体物质和合成材料来重建颅骨缺损都是次优的。这些不足为我们的应用提供了动力。通过鉴定具有天生优越成骨能力的颅骨，我们寻求洞察到强健的颅骨再生的新策略。在具体目标1中，我们将确定成纤维细胞生长因子信号在调节神经沟来源的额骨和旁轴中胚层来源的顶骨成骨细胞之间的差异中所起的作用。将首先比较上述野生型和转基因小鼠的额骨和顶骨之间关键的成纤维细胞生长因子配体和受体的表达谱及其下游介体的激活情况。在特定的目标2中，我们将确定在野生型小鼠损伤后添加外源性的成纤维细胞生长因子-2、-9和-18是否增强了近轴中胚层来源的顶骨减少的愈合能力。在特定的目标3中，我们将确定在带有成纤维细胞生长因子-2-/-、-9-/-和-18-/-功能突变的转基因小鼠中，神经脊来源的额骨的强大愈合能力是否降低或被否定。最终，这项应用的翻译目标是确定成纤维细胞生长因子家族中促进强健骨再生的关键分子机制。我们断言，鉴定具有优越成骨能力的颅骨将为深入了解这种机制提供帮助。

DESCRIPTION (provided by applicant): We put forward that the unique embryological origins of individual mammalian calvaria impact differences in their osteogenic capacity. The cental hypothesis of this proposal is that differences in embryonic origins of calvarial osteoblasts affect their embryonic and post-natal osteogenic potential and skeletal regenerative capacity. The paired parietal frontal bones in the anterior skull are derived from the neural crest and the paired parietal bones, positioned posteriorly, are derived from the paraxial mesoderm. We have preliminarily observed the frontal bone to possess superior osteogenic potential both in vitro and in vivo compared to the parietal bone. Our proposal aims to verify this difference in osteogenic potential and elucidate the role of fibroblast growth factor (FGF) signaling underlying this disparity. Such an understanding is of central importance to overcoming current challenges with treatment of calvarial defects. The inability of humans older than one year of age to reossify calvarial defects poses a substantial burden on our healthcare system. Current use of autogenous grafts, allogeneic substances, and synthetic materials to reconstruct calvarial defects are all suboptimal. These inadequacies serve as the impetus for our application. Through the identification of calvarial bones with inherently superior osteogenic capacity, we seek to gain insight into novel strategies for robust calvarial regeneration. In Specific Aim 1, we will determine the role of FGF signaling in mediating differences between neural crest-derived frontal and paraxial mesoderm-derived parietal bone osteoblasts. Will begin by comparing the expression profile of key FGF ligands and receptors, and the activation of their downstream mediators, between the frontal and parietal bones of the wild-type and transgenic mice described above. In Specific Aim 2, we will determine if the reduced healing capacity of paraxial mesoderm-derived parietal bone is augmented by the addition of exogenous FGF-2, -9, and -18 after injury in wild-type mice. In Specific Aim 3, we will determine if the robust healing capacity of neural crest-derived frontal bone is reduced or negated in transgenic mice possessing fgf-2-/-, -9-/-, and -18-/- loss of function mutations. Ultimately, the translational goal of this application is to identify key molecular mechanisms in the FGF family that promote robust bone regeneration. We assert that the identification of calvarial bones with superior osteogenic capacity will provide insight into such mechanisms.