Cell Differentiation in Periodontal Regeneration

描述(申请人提供)：创伤和先天性疾病会导致口腔颌面部的骨和软组织缺陷。牙周病导致牙槽骨破坏和牙齿脱落。这些疾病的最终治疗目标是组织再生，这需要(1)修复细胞的分化和(2)细胞外基质成分的产生。我们的长期目标是扩大目前对牙周组织形成和再生所涉及的细胞和分子机制的了解，并为骨骼再生和组织工程产品的开发提供进一步的见解。这项应用的目的是确定参与组织修复和再生过程的细胞的分化潜力。需要验证的中心假设是，在牙周再生过程中，转录因子Cbfa1选择性地诱导成骨和成牙骨质分化，并随后表达BSP，从而促进组织形成和矿化。其理论基础是有证据表明，将未分化的间充质细胞和成骨前细胞转化为成熟的、有功能的成骨细胞是骨形成和骨再生的关键步骤。目的1.在体内研究Cbfa1在牙周再生过程中对细胞分化的调节和促进作用。利用基因治疗的方法，首次将“主控基因”Cbfa1引入到人工造成的牙周缺陷中，并记录其诱导和调节作用。目的2.确定分化细胞表达的BSP在河床骨组织形成和再生过程中促进矿化的作用。利用基于细胞的方法，将BSP高表达细胞移植到牙周缺损区，并首次确定了BSP在促进体内生物矿化和骨成熟方面的作用。RIVE研究的结果将为成骨基因治疗和细胞分化的分子控制提供新的和重要的见解，细胞分化是组织形成和牙周再生的最重要组成部分和最强大的引擎。

DESCRIPTION (provided by applicant): Traumas as well as congenital disorders cause bone and soft tissue defects in oral and maxillofacial region. Periodontal disease results in destruction of alveolar bone and tooth loss. The ultimate therapeutic goal for these diseases is tissue regeneration, which requires (1) differentiation of reparative cells and (2) production of extracellular matrix components. Our long-range goal is to expand current understanding of the cellular and molecular mechanisms involved in formation and regeneration of periodontal tissues and to provide further insight into the development of products for skeletal regeneration and tissue engineering. The objective of this application is to determine differentiation potential of cells involved in the processes of tissue repair and regeneration. The central hypothesis to be tested is that, in periodontal regeneration, the transcription factor Cbfa1 selectively induces osteogenic and cementogenic differentiation and the subsequent expression of BSP which enhances tissue formation and mineralization. The rationale is based on evidence that the conversion of non-differentiated mesenchymal cells and pre-osteoblastic cells into mature and functional osteoblasts is a crucial step in bone formation, as well as in bone regeneration. Aim 1. To determine in vivo the regulating and promoting effects of Cbfa1 in cell differentiation occurring during periodontal regeneration. Using a gene-therapy approach, for the first time, the "master gene" Cbfa1, will be introduced into an artificially created periodontal defect and its inductive and modulating effects documented. Aim 2. To determine the role of BSP expressed by differentiated cells in enhancing mineralization in the process of bone tissue formation and regeneration in rive. Using a cell-based method, BSP overexpressing cells will be transplanted into periodontal defects and for the first time the effect of BSP in enhancing biomineralization and bone maturation in vivo determined. Results derived from these in rive studies should provide novel and important insights into osteogenic gene therapy and molecular control of differentiation of cells, the most important component and the most powerful engine in tissue formation and periodontal regeneration.