Regional differences in neural crest and mesodermal derived calvarial bone healin

神经嵴和中胚层来源的颅骨愈合的区域差异

基本信息

批准号：
8415477
负责人：
MICHAEL T LONGAKER
金额：
$ 36.45万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-12 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415477
关键词：
1 year old ARHGEF5 gene Address Adult Affect Age Allogenic Anterior Attention Biology Bone Development Bone Regeneration Calvaria Cells Cellular biology Cephalic Collagen Data Defect Elements Embryo Environment Family Fibroblast Growth Factor Fibroblast Growth Factor 2 Foundations Frontal bone structure Galactosidase Gene Expression Profile Goals Healed Healthcare Systems Human Impaired wound healing Implant In Vitro Individual Injury Investigation Knowledge Laboratories Left Ligands Mediating Mediator of activation protein Modality Molecular Molecular Biology Molecular Profiling Mus Natural regeneration Neural Crest Operative Surgical Procedures Osteoblasts Osteogenesis Paraxial Mesoderm Parietal Parietal bone structure Phenotype Play Porifera Positioning Attribute Process Proteins Receptor Activation Regulation Relative (related person)Role Secondary to Signal Pathway Signal Transduction Signaling Molecule Staining method Stains Tissue Engineering Tissue Stains Tissues Transgenic Mice Translating Wild Type Mouse base bone bone healing cranium healing improved in vivo insight interest loss of function mutation millimeter novel strategies osteoblast differentiation osteogenic public health relevance ranpirnase receptor regenerative regional difference research study skeletal skeletal tissue

项目摘要

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.

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。该提议的中心假设是颅骨成骨细胞胚胎起源的差异影响其胚胎和出生后的成骨潜力和骨骼再生能力。前颅骨中的成对顶骨额骨源自神经嵴，而位于后面的成对顶骨源自轴旁中胚层。我们初步观察到，与顶骨相比，额骨在体外和体内均具有优越的成骨潜力。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）信号传导在这种差异背后的作用。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再骨化颅骨缺陷，这给我们的医疗保健系统带来了沉重负担。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的方法都不是最理想的。这些不足成为我们申请的动力。通过识别具有固有优越成骨能力的颅骨，我们寻求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叶和轴旁中胚层来源的顶骨成骨细胞之间差异中的作用。首先将比较上述野生型和转基因小鼠的额骨和顶骨之间关键 FGF 配体和受体的表达谱及其下游介质的激活。在具体目标 2 中，我们将确定野生型小鼠受伤后添加外源 FGF-2、-9 和 -18 是否会增强近轴中胚层来源的顶骨愈合能力的降低。在具体目标 3 中，我们将确定在 fgf-2-/-、-9-/- 和 -18-/- 功能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降低或消失突变。最终，该应用的转化目标是确定 FGF 家族中促进强健骨再生的关键分子机制。我们断言，鉴定具有卓越成骨能力的颅骨将有助于深入了解此类机制。