Molecular Mechanisms of Nickel-induced Tumorigenicity.

描述（由申请人提供）：本竞争性更新申请将继续研究镍化合物介导肺癌发生的分子机制。特别是，该提案旨在确定连接镍诱导的肺持续炎症的人支气管上皮细胞（HBEC）在体外和体内的致瘤性的分子机制。尽管镍诱导的持续性气道炎症与肺癌的发生之间存在联系，但镍暴露与持续性肺部慢性炎症之间的分子机制尚不清楚。从上一个资助期获得的研究和初步研究表明，镍暴露导致核因子-：B（NF：B）活化，进而介导考克斯-2诱导。我们的研究还表明，镍暴露能够激活AP-1，这反过来又介导TNF-1的诱导。此外，我们发现，TNF-1能够通过NFAT依赖性途径诱导考克斯-2。此外，我们发现，有串扰之间的NFAT和NF？细胞对镍暴露反应过程中的B途径。因此，这个更新建议的主要假设是，NFAT/ NF？B活化和促炎性TNF-1和考克斯-2诱导将形成正性炎症反馈环，其负责形成和维持持续的慢性肺部炎症和由于镍暴露而诱导肺上皮细胞致瘤性。我们提出以下具体目的：1），验证炎症正反馈回路是由NF？B、NFAT和TNF 1是维持镍暴露对HBECs持续的考克斯-2诱导的重要因素; 2）确定正性炎症反馈环在镍暴露诱导HBECs致瘤性发展中的作用。（3）探讨TNF-1在镍诱导的慢性肺炎症中的作用及其机制。这项建议的总体目标是澄清之间的NFAT，NF？B、TNF-1和考克斯-2在体内和体外镍暴露中的作用，并确定正性炎症反馈环在镍诱导的HBEC致瘤性中的作用，以及TNF-1在体内镍暴露期间维持肺持续慢性炎症和肺癌发生中的中心作用。该提案的成功将有助于我们理解导致肺部慢性炎症微环境形成和维持的分子机制，以及其在镍暴露导致的肺癌发生中的作用。更好地了解这些问题可能会提供有价值的信息，设计更有效的药物，用于预防和治疗肺癌。我们认为，提出的贡献积极的炎症反馈回路负责镍诱导的肺致瘤性是新颖的。

DESCRIPTION (provided by applicant): This competitive renewal application will continue examining the molecular mechanisms by which nickel compounds mediate lung carcinogenesis. In particular, this proposal seeks to identify the molecular mechanisms linking nickel-induced lung sustained inflammation to tumorigenicity of human bronchial epithelial cells (HBECs) in vitro and in vivo. Although there is an association between nickel- induced sustained airway inflammation and lung cancer development, the molecular mechanisms linking nickel exposure to the sustained lung chronic inflammation are not understood yet. The studies obtained from the last funding period and preliminary studies demonstrate that nickel exposure results in the activation of the nuclear factor-:B (NF:B), which in turn mediates COX-2 induction. Our studies also show that nickel exposure enables activation of AP-1, which in turn mediates TNF-1 induction. Furthermore, we find that TNF-1 enables COX-2 induction through the NFAT-dependent pathway. In addition, we find that there is crosstalk between the NFAT and NF?B pathways during cellular response to nickel exposure. Thus, the main hypothesis of this renewal proposal is that the NFAT/ NF?B activation and the pro-inflammatory TNF-1 and COX-2 induction will form positive inflammatory feedback loops, which are responsible for the formation and maintenance of sustained chronic lung inflammation and the induction of lung epithelial cell tumorigenicity due to nickel exposure. We propose the following Specific Aims: 1), To test the hypothesis that the inflammatory positive feedback loops being formed by NF?B, NFAT, and TNF1 are responsible for the maintenance of sustained COX-2 induction due to nickel exposure in HBECs; 2), To determine the role of the positive inflammatory feedback loops in the development of tumorigenicity induced by nickel exposure in HBECs.; 3), To assess the central role of TNF-1 in nickel-induced chronic lung inflammation and its mechanisms in vivo. The overall goal of this proposal is to clarify the formation of positive inflammatory feedback loops among NFAT, NF?B, TNF-1 and COX-2, in nickel exposure both in vitro and in vivo, and to determine the role of the positive inflammatory feedback loops in nickel-induced HBECs' tumorigenicity, as well as the central role of TNF-1 in the maintenance of lung sustained chronic inflammation and lung carcinogenesis during nickel exposure in vivo. Success of the proposal will facilitate our understanding of the molecular mechanism(s) that lead to the formation and maintenance of a lung chronic inflammatory microenvironment, and its role in lung carcinogenesis due to nickel exposure. A better understanding of these issues may provide valuable information for the designing of more effective agents for the prevention and therapy of lung cancers. We believe that the proposed contribution of positive inflammatory feedback loop responsible for nickel-induced lung tumorigenicity is novel.