Mechanisms of Cadmium Toxicity in Epithelial Cells

说明(申请人提供)：镉(CD2)是一种重要的工业和环境污染物，可对肺、肾、肝、骨等多种器官造成严重损害。此外，CD2已被证明具有致畸和致癌活性。尽管CD2作为一个环境健康问题很重要，但人们对CD2产生不利影响的具体细胞和分子机制知之甚少。该项目的长期目标是确定其中一些机制。来自文献的证据表明，CD2在体内的一些作用可能是由于破坏了不同上皮和内皮表面细胞之间的连接而产生的。最近的研究结果表明，CD2可以选择性地破坏培养中各种类型的上皮细胞之间的钙依赖连接，这些作用很可能是由于CD2与钙依赖的细胞黏附分子E-钙粘附素的相互作用所致。最近的更多研究表明，CD2可以破坏E-钙粘素和VE-钙粘素依赖的细胞-细胞连接，并改变E-钙粘素和N-钙粘素在肾脏中的定位。在培养的细胞上的其他结果表明，钙粘附素介导的黏附的丧失导致钙粘附素结合蛋白β-连环素从连接复合体移位到细胞核，并可能导致基因表达的改变。这些结果表明，钙粘附素/β-连环素复合体可能是CD2在肺和肾上皮细胞中毒性的一个重要的早期靶点。本提案中描述的工作是这些先前研究的直接延伸，旨在解决两个主要问题。第一个目标是继续正在进行的研究，检测CD2对体内钙粘附素/连环蛋白复合体的影响，并确定这一机制是否可能与CD2在特定靶器官如肺和肾脏的毒性作用有关，这些器官是CD2毒性的重要靶点。第二个目的是研究CD2诱导的钙粘附素/β-连环蛋白复合体的破坏可能导致β-连环蛋白从连接复合体移位到细胞核，并改变β-连环蛋白调控的基因表达。这些问题将通过采用包括体外和体内研究的多学科方法来解决，这些研究利用了各种生理、形态和生化技术。这些研究的结果应该会为CD2产生某些毒性效应的机制提供重要的新见解。此外，这些研究的结果可能会对有毒物质影响生物的机制产生更广泛的影响。

DESCRIPTION (provided by applicant): Cadmium (Cd2+) is an important industrial and environmental pollutant that can cause severe damage to a variety of organs including the lung, kidney, liver, and bone. In addition, Cd2+ has been shown to have teratogenic and carcinogenic activities. In spite of its importance as an environmental health problem, relatively little is known about the specific cellular and molecular mechanisms by which Cd2+ produces its adverse effects. The long-term objective of this project is to identify some of these mechanisms. Evidence from the literature suggests that some of the effects of Cd2+ in vivo may result from the disruption of the junctions between cells in various epithelial and endothelial surfaces. Results of recent studies have shown that Cd2+ can selectively disrupt the Ca2+-dependent junctions between various types of epithelial cells in culture, and that these effects most likely result from the interaction of Cd2+ with the Ca2+-dependent cell adhesion molecule, E-cadherin. More studies that are recent have shown that Cd2+ can disrupt E-cadherin- and VE-cadherin-dependent cell-cell junctions in the lung and alter the localization of E-cadherin and N-cadherin in the kidney. Additional results on cells in culture suggest that the loss of cadherin-mediated adhesion results in the translocation of the cadherin-binding protein beta-catenin from the junctional complexes to the cell nucleus and possible alterations in gene expression. These results suggest that the cadherin/beta-catenin complex may be an important early target of Cd2+ toxicity in epithelial cells of the lung and kidney. The work described in this proposal is a direct extension of these previous studies, and is aimed at resolving two major issues. The first objective is to continue ongoing studies examining the effects of Cd2+ on the cadherin/catenin complex in vivo, and to determine if this mechanism might contribute to the toxic effects of Cd2+ in specific target organs such as the lung and the kidney, which are important targets of Cd2+ toxicity in humans. The second objective is to examine the possibility that the Cd2+-induced disruption of the cadherin/beta-catenin complex may lead to the translocation of beta-catenin from the junctional complexes to the nucleus and alterations in beta-catenin-regulated gene expression. These issues will be addressed by employing a multidisciplinary approach that includes both in vitro and in vivo studies that utilize a variety of physiologic, morphologic and biochemical techniques. Results of these studies should provide important new insights into the mechanisms by which Cd2+ produces some of its toxic effects. Furthermore, the results of these studies could have more general implications regarding the mechanisms by which toxic substances affect living organisms.