Matrix-assisted Craniofacial Bone Regeneration

描述（由申请人提供）：高质量的有效骨重建对于牙科植入物、牙周再生和骨缺损治疗的成功至关重要。本研究的目的是开发一种基于骨中基质蛋白聚糖（biglycan，BGN）独特功能的有效骨再生方法。我们已经证明，BGN加速成骨细胞分化和基质矿化在体外和克隆过表达BGN有效地产生高度组织化的矿化基质后，他们移植到免疫缺陷小鼠。这种功能可能部分是由于BGN核心蛋白的独特能力，“积极”调节特定的骨形态发生蛋白（BMP）的功能。基于这些和其他初步数据，我们假设BGN核心蛋白的特定结构域，即效应结构域，发挥这种独特的功能，并能够促进体内高质量骨的形成。为了验证这一假设，提出了两个具体的目标：在目标1中，我们将通过产生几种BGN核心蛋白衍生的构建体并评估其体外促进BMP-2功能、成骨细胞分化和矿化的能力来鉴定效应结构域，在目标2中，我们将使用大鼠下颌骨缺损模型测试BGN/效应结构域是否可以在体内促进骨形成。本研究的结果可能会为有效的、新型的基质辅助骨形成提供见解，并可能有助于开发治疗骨缺损的新治疗策略。 公共卫生相关性：在我们的老龄化社会中，越来越多的人口患有颅面骨缺损。鉴于严重受损的生活质量和现有治疗的局限性，开发新的治疗策略至关重要。为此，本研究将探索一种基于骨基质分子biglycan的独特功能的有效且具有成本效益的颅面骨再生新方法。

DESCRIPTION (provided by applicant): Efficient reconstruction of bone with high quality is critical for the success of dental implants, periodontal regeneration and treatments of bone defects in general. The goal of this study is to develop a means for efficient bone regeneration based on a unique function of a matrix proteoglycan in bone, biglycan (BGN). We have demonstrated that BGN accelerates osteoblast differentiation and matrix mineralization in vitro and that clones overexpressing BGN efficiently produced highly organized mineralized matrix upon their transplantation into immunodeficient mice. This function could be due in part to the unique ability of the BGN core protein to "positively" modulate the functions of specific bone morphogenetic proteins (BMPs). Based on these and other preliminary data, we hypothesized that the specific domain of BGN core protein, i.e. the effector domain, exerts this unique function and is capable of promoting the formation of bone with high quality in vivo. To test this hypothesis, two specific aims are proposed: in Aim 1, we will identify the effector domain by generating several BGN core protein-derived constructs and evaluating their capabilities to promote BMP-2 function, osteoblast differentiation and mineralization in vitro, and in Aim 2, we will test if the BGN/effector domain can promote bone formation in vivo employing a rat mandible defect model. The results of this study may provide insights into an effective, novel matrix-assisted bone formation and may help develop new therapeutic strategies for treating bone defects. PUBLIC HEALTH RELEVANCE: A growing population of our aging society is suffering from craniofacial bone defects. Given the severely impaired quality of life and limitations of current treatments, development of new therapeutic strategies is of critical importance. Towards this end, this study will explore a novel approach to efficient and cost-effective craniofacial bone regeneration based on a unique function of bone matrix molecule, biglycan.