Regional differences in neural crest and mesodermal derived calvarial bone healin

描述（由申请人提供）：我们提出个体哺乳动物颅骨的独特胚胎起源影响其成骨能力的差异。该建议的中心假设是，颅骨成骨细胞的胚胎来源的差异影响其胚胎和出生后成骨潜能和骨骼再生能力。前颅骨成对的顶骨来源于神经嵴，位于后方的成对顶骨来源于近轴中胚层。我们已经初步观察到额骨与顶骨相比，在体外和体内都具有优越的成骨潜力。我们的研究旨在验证这种成骨潜能的差异，并阐明成纤维细胞生长因子（FGF）信号在这种差异中的作用。这样的理解对于克服目前治疗颅骨缺损的挑战是至关重要的。一岁以上的人无法对颅骨缺损进行再骨化，这对我们的医疗保健系统造成了沉重的负担。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不理想的。这些不足之处是我们申请的动力。通过鉴定颅骨具有先天优越的成骨能力，我们寻求深入了解强健颅骨再生的新策略。在Specific Aim 1中，我们将确定FGF信号在介导神经嵴来源的额叶和旁轴中胚层来源的顶骨成骨细胞差异中的作用。我们将首先比较上述野生型和转基因小鼠额骨和顶骨中关键FGF配体和受体的表达谱及其下游介质的激活。在特异性目标2中，我们将确定在野生型小鼠损伤后，外源性FGF-2、-9和-18是否会增强近轴中胚层来源顶骨的愈合能力。在Specific Aim 3中，我们将确定在具有fgf-2-/-、-9-/-和-18-/-功能突变丧失的转基因小鼠中，神经嵴来源的额骨的强大愈合能力是否会降低或被否定。最终，该应用的翻译目标是确定FGF家族中促进强健骨再生的关键分子机制。我们断言，鉴定颅骨具有优越的成骨能力将提供深入了解这种机制。

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.