Role of system xc- in dental pulp survival and death

 描述(申请人提供)：当牙髓细胞暴露在环境中时，无论是由于创伤、快速发展的龋齿，还是过于激进的修复过程，都需要进行重要的牙髓治疗，以试图防止这些细胞的死亡。如果这一过程失败，将来将需要根管治疗。在活髓治疗过程中，使用盖髓材料。盖髓材料的目的是刺激在暴露的牙髓上形成牙本质桥。含有氢氧化钙的材料被广泛用于盖髓，因为它们能够刺激修复性牙本质的形成。然而，氢氧化钙被发现对牙髓细胞有毒性。关于盖髓治疗成功率的报道差异很大，很明显，在实际的牙科实践中 目前的程序并不总是有效的。氢氧化钙化合物的一种潜在替代或辅助方法是在盖髓过程中使用生长因子。生长因子已经被证明可以诱导修复性牙本质的形成，我们已经证明它们可以保护牙髓细胞免受多种类型的伤害所引起的毒性。重要的是，我们发现生长因子的保护作用是由于它们上调半胱氨酸/谷氨酸逆向转运蛋白(系统XC-)的能力。系统XC-介导两个重要的作用：摄取半胱氨酸和释放谷氨酸。摄取半胱氨酸是细胞内主要的自由基清除剂谷胱甘肽产生的限速步骤。这一发现代表了生长因子对牙髓细胞影响的新机制，并建议在评估各种因素对牙髓细胞的影响时，将XC-系统的调节作为一个关键变量进行探索。需要检验的假设是，系统XC功能的改变是盖髓材料成功的决定因素。特异靶1的实验旨在彻底了解牙髓细胞中XC-系统的调节因素，以及这种调节如何影响细胞培养中的存活。具体目标2的目标是确定XC系统活性的改变是否决定了盖髓材料的成功。从这些研究中获得的信息将提供对XC-系统的监管如何发生以及该监管的后果的理解。其想法是，由于XC-系统在维持细胞谷胱甘肽水平方面发挥着重要作用，因此在确定使用与牙髓细胞相互作用的材料时，应考虑了解物质如何改变其表达和功能。

 DESCRIPTION (provided by applicant): When dental pulp cells are exposed to the environment, whether it is due to trauma, rapidly progressing caries, or overly aggressive restoration procedures, vital pulp therapy is required to attempt to prevent the death of those cells. If this procedure fails a root canal will be required in the future. During vital pulp theray a pulp capping material is used. The objective of the pulp capping material is to stimulate the formation of a dentin bridge over the exposed pulp. Calcium hydroxide containing materials are widely used for pulp capping because of their ability to stimulate reparative dentin formation. However, calcium hydroxide has been found to be toxic to dental pulp cells. Reports of the success rate of pulp capping treatments vary greatly and it is clear that in actual dental practice current procedures are not always effective. A potential alternative, or adjunct, to calcium hydroxide compounds is the use of growth factors during pulp capping procedures. Growth factors have been shown to induce the formation of reparative dentine and we have shown that they can protect dental pulp cells against toxicity induced by a number of types of insults. Importantly, we found that the protective effects of growth factors are due to their ability to upregulate the cystine/glutamate antiporter (system xc-). System xc- mediates two important actions: the uptake of cystine and the release of glutamate. The uptake of cystine is the rate limiting step in the production of the main intracellular free radical scavenger glutathione. This finding represents a novel mechanism of growth factor effects on dental pulp cells and suggests regulation of system xc- as a key variable to explore when assessing impact of various factors on dental pulp cells. The hypothesis to be tested is that alteration in system xc- function is a determining factor in the success of pulp capping materials. The experiments of Specific Aim 1 are designed to thoroughly understand the factors that regulate system xc- in dental pulp cells and how that regulation effects their survival in cell culture. The goal of Specific Aim 2 is to determine if altered activity of system xc- determines the success of pulp capping materials. The information obtained from these studies will provide an understanding of how regulation of system xc- occurs and the consequences of that regulation. The idea being that because of the important role that system xc- plays in the maintenance of cellular glutathione levels, understanding how substances alter its expression and function should be taken into consideration whenever determining the use of materials that interact with dental pulp cells.