Role of complement receptor C5L2 in reparative dentinogenesis

项目概要/摘要 龋齿是一种常见的公共卫生问题。龋病涉及细菌侵入、物理化学 牙齿的矿物质和蛋白质成分的溶解和蛋白质水解。直接细菌和副产物 牙本质龋中与牙髓细胞和成牙本质细胞的相互作用激活了牙本质的保护性修复过程 “三级”牙本质形成。这一过程需要牙髓干细胞的募集和分化 （私营保安公司）。盖髓术等临床治疗方法旨在促进牙本质再生，维持牙髓活力 以及自然牙列的耐久性。然而，治疗性牙本质再生是难以捉摸的。的 感染后牙本质牙髓再生的细胞和分子机制还不完全 阐明，特别是炎症对牙本质形成的作用。我们已经证明， 系统是炎症和组织再生的重要介质，在龋中被激活 过程补体和C5 a与其受体C5 aR结合在损伤应答中的主要作用是很好的。 确立了习C5 a受体样蛋白2（C5 L2）也参与了多种病理性炎症反应。 然而，到目前为止，还没有研究探索这种神秘的受体在组织再生中的作用。 和干细胞生物学在此，我们提出补体系统和C5 L2在DPSC中的重要作用 成牙本质细胞分化和修复性牙本质形成。初步研究表明，C5 L2 在牙源性分化过程中，DPSC的表达迅速增加， 炎症细胞因子TNFα。此外，siRNA沉默DPSC中C5 L2的表达显著降低了DPSC中C5 L2的表达。 在牙本质分化过程中增加牙本质标记物如DMP 1和DSPP的表达。我们 进一步证明p38 map激酶（p38 a）在DPSC介导的牙本质形成中起关键作用。在这里， 我们探索了通过一种新的涉及p38 a的C5 L2途径来增强DPSCs的成牙本质细胞功能的方法。 发信号。我们将明确C5 L2在DPSC成牙本质细胞分化中的作用，并描述其在DPSC分化中的作用。 C5 L2在牙本质形成过程中的作用机制。将使用小鼠评价体内牙本质形成。 C5 aR、C5 L2和DSPP/p38 a基因敲除小鼠的盖髓/龋齿模型。获得的结果 从这个项目将揭示新的光到细胞和分子事件，协调的初始步骤， 通过C5 L2和p38 a途径将炎症与DPSC功能联系起来，从而促进牙本质形成。这些研究 将为将来潜在的牙本质牙髓复合体再生和重要的治疗干预提供基础。 牙齿保护

Project Summary/Abstract Dental caries represents a common public health problem. Caries involves bacterial invasion, physicochemical dissolution and proteolysis of the mineral and protein components of teeth. Direct bacterial and byproduct interaction with dental pulp cells and odontoblasts in dentinal caries activates a protective repair process of ‘tertiary’ dentin formation. This process requires the recruitment and differentiation of dental pulp stem cells (DPSCs). Clinical therapies such as pulp capping aim to promote dentin regeneration and sustain pulp vitality and consequently endurance of the natural dentition. However, therapeutic dentin regeneration is elusive. The cellular and molecular mechanisms orchestrating dentin-pulp regeneration following infection are not fully elucidated, especially the role of inflammation on dentinogenesis. We have demonstrated that the complement system, which is an important mediator of inflammation and tissue regeneration, is activated in the caries process. A major role for complement and C5a binding to its receptor C5aR in responses to injury is well established. The C5a receptor- like 2 (C5L2) also participated in inflammatory reactions of several pathological conditions, yet, to date no investigation has explored the role of this enigmatic receptor in tissue regeneration and stem cell biology. Here, we propose a significant role for the complement system and C5L2 in DPSC odontoblastic differentiation and reparative dentin formation. Preliminary studies demonstrate that C5L2 expression by DPSCs is quickly increased during odontogenic differentiation, and this expression is potentiated by the inflammatory cytokine TNFα. Moreover, siRNA silencing of C5L2 expression in DPSCs significantly increases the expression of dentinogenic markers like DMP1 and DSPP during odontogenic differentiation. We provide further evidence that p38 map kinase (p38a) plays a key role in DPSC-mediated dentinogenesis. Here, we explore ways of enhancing this odontoblastic function of DPSCs via a novel C5L2 pathway involving p38a signaling. We will define the role of C5L2 in the odontoblastic differentiation of DPSC and characterize the mechanism of action of C5L2 during dentinogenesis. In vivo dentin formation will be evaluated using the mouse pulp-capping/caries model combined with the C5aR, C5L2 and DSPP/p38a knockout mice. The results obtained from this project will shed new light onto cellular and molecular events that orchestrate the initial steps of dentinogenesis by linking the inflammation to DPSC function through C5L2 and p38a pathways. These studies will provide the basis for future potential therapeutic interventions of dentin-pulp complex regeneration and vital tooth preservation.