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学起源影响其成骨能力的差异。本研究的核心假设是颅骨成骨细胞的胚胎起源差异影响其胚胎和出生后的成骨潜能和骨骼再生能力。前头骨中的成对顶骨额骨来自神经嵴，位于后方的成对顶骨来自轴旁中胚层。我们已经初步观察到额骨具有上级的成骨潜力，无论是在体外和体内相比，顶骨。我们的建议旨在验证成骨潜力的这种差异，并阐明成纤维细胞生长因子（FGF）信号转导的作用，这种差异的基础。这种理解对于克服当前颅骨缺损治疗的挑战至关重要。一岁以上的人类无法使颅骨缺陷重新骨化，这对我们的医疗保健系统造成了巨大的负担。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。这些不足之处是我们申请的动力。通过鉴定具有内在上级成骨能力的颅骨，我们试图深入了解强健颅骨再生的新策略。在具体目标1中，我们将确定FGF信号传导在介导神经嵴来源的额骨和近轴中胚层来源的顶骨成骨细胞之间的差异中的作用。将开始通过比较关键的FGF配体和受体的表达谱，以及它们的下游介质的激活，在上述野生型和转基因小鼠的额骨和顶骨之间。在特定目标2中，我们将确定在野生型小鼠损伤后，加入外源性FGF-2、FGF-9和FGF-18是否能增强近轴中胚层来源的顶骨的愈合能力。在具体目标3中，我们将确定在具有fgf-2-/-、-9-/-和-18-/-功能缺失突变的转基因小鼠中，神经嵴来源的额骨的稳健愈合能力是否降低或被否定。最终，本申请的翻译目标是确定FGF家族中促进稳健骨再生的关键分子机制。我们断言，具有上级成骨能力的颅骨的鉴定将提供对这种机制的深入了解。 公共卫生相关性：头骨的各个骨骼来自胚胎的不同部分。我们的申请旨在调查这种起源上的差异是否会转化为他们愈合颅骨缺损能力的差异。此外，我们的申请旨在阐明上级骨愈合的机制。这与改善当前用于重建颅骨缺损的治疗方式直接相关。颅骨缺陷是美国医疗系统的重大生物医学负担。目前采用了无数的重建方案，每一种方案都有其固有的不足之处。鉴定具有上级愈合潜力的颅骨提供了对可用于再生而不是重建颅骨的新策略的深入了解。

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. PUBLIC HEALTH RELEVANCE: The individual bones of the skull originate from different parts of the embryo. Our application aims to investigate whether this dissimilarity in origin translates into differences in their ability to heal skull defects. Furthermore, our application aims to elucidate the mechanisms underlying superior bone healing. This is of direct relevance to improving current treatment modalities for reconstructing skull defects. Defects in the skull represent a substantial biomedical burden on the US healthcare system. A myriad of reconstructive options are currently employed, each with their inherent inadequacies. Identification of skull bones with superior healing potential provides insight into novel strategies that can be employed to regenerate, rather than reconstruct, skull bones.