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Molecular Mechanisms of Nickel-Induced Tumorigenicity

镍致肿瘤的分子机制

基本信息

批准号：
7450914
负责人：
CHUANSHU HUANG
金额：
$ 29.56万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7450914
关键词：
Affect Animal Model Breathing Calcineurin Cancer Etiology Cell Nucleus Cells Chemoprevention Complement Factor B Control Groups Data Development Dominant-Negative Mutation Dose Electron Spin Resonance Spectroscopy Embryo Enzymes Epithelial Cells Event Exposure to Fibroblasts Fluorescent Dyes Gene Expression Regulation Generations Goals Human In Vitro Irrigation Left lung Liquid substance Luciferases Lung Neoplasms Malignant Neoplasms Manganese Superoxide Dismutase Measurement Measures Mediating Mediator of activation protein Mitochondria Molecular Mus NF-AT Nickel Nose Nuclear Nuclear Translocation Nude Mice Pathology Pathway interactions Peptides Personal Satisfaction Plasmids Play Prevention therapy Protein Isoforms Protein Overexpression Proteins Publishing Range Reactive Oxygen Species Reporter Reporting Research Research Personnel Right lung Role Signal Transduction Signal Transduction Pathway Staining method Stains T-Cell Activation Techniques Testing Time Toxic effect Transactivation Transfection Transgenic Mice Transgenic Model Tumor Promotion Tumorigenicity activating transcription factor base carcinogenesis carcinogenicity catalase cell transformation cell type design diacetyldichlorofluorescein exposed human population in vivo in vivo Model indexing inhibitor/antagonist neutrophil nuclear factors of activated T-cells particle programs response titanium dioxide transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The carcinogenicity of nickel compounds has been well documented by studies both in vitro and in vivo. However, the molecular mechanisms by which nickel compounds cause cancer are not well understood. It is accepted that the tumor promotion effects of nickel compounds occur through regulation of gene expression, which is mediated by activated transcription factors. A nuclear factor of activated T cells (NFAT) and nuclear factor-(B (NF(B) are transcription factors, which are believed to play an important role in cancer development. Our preliminary data show that nickel compounds are able to induce activation of NFAT and NF(B in human bronchoepithelial cells. Therefore, the main hypothesis of this proposal is that NFAT and NF(B play a critical role in nickel-induced tumorigenicity in human bronchial epithelial cells (HBECs). The overall goal of this proposal is to study the molecular mechanisms by which nickel compounds mediate carcinogenesis. In particular, this proposal seeks to identify the initiating signaling leading to activation of transcription factors NFAT and NF(B, and their roles in nickel-induced tumorigenicity of human bronchial epithelial cells. Thus, we will investigate this issue in accordance with the following specific aims: 1) To test the hypothesis that reactive oxygen species (ROS) are involved in activation of transcription factor NFAT and NF(B in HBECs in response to nickel compounds; 2) To elucidate the role of NFAT activation in nickel-induced tumorigenicity of HBECs; 3) To test the hypothesis that NF(B transactivation is an important player in nickel-induced tumorigenicity in HBECs; 4) To establish the in vivo effects of nickel compounds on NFAT and NF(B activation by using NFAT and NF(B-luciferase transgenic mice. The significance of the research proposed in this application is that the results derived from the proposed studies will greatly facilitate the understanding of the molecular mechanism of carcinogenic effects of nickel compounds. This study will also provide in vivo models to further investigate the role of NFAT and NF(B activation in nickel-induced carcinogenesis in vivo. Furthermore, it will also help us to determine whether we can use NFAT or NF(B as targets for chemoprevention of nickel-induced carcinogenesis.

描述（由申请人提供）：镍化合物的致癌性已通过体外和体内研究得到充分证明。然而，镍化合物致癌的分子机制尚不清楚。人们普遍认为，镍化合物的肿瘤促进作用是通过调节基因表达来实现的，而基因表达是由激活的转录因子介导的。活化T细胞核因子(NFAT)和核因子-(B(NF(B))是转录因子，被认为在癌症发展中发挥重要作用。我们的初步数据表明，镍化合物能够诱导人支气管上皮细胞中NFAT和NF(B的活化。因此，该提议的主要假设是NFAT和NF(B在镍诱导的癌症发生中起关键作用。人支气管上皮细胞（HBEC）的致瘤性。该提案的总体目标是研究镍化合物介导致癌的分子机制。特别是，该提案旨在确定导致转录因子 NFAT 和 NF(B 激活) 的起始信号传导，及其在镍诱导的人支气管上皮细胞致瘤性中的作用。因此，我们将根据以下具体目标来研究这个问题：1）检验活性氧（ROS）参与HBEC中转录因子NFAT和NF（B在镍化合物响应中的激活）的假设；2）阐明NFAT激活在镍诱导的HBEC致瘤性中的作用； 3) 检验 NF(B 反式激活是一个重要的镍诱导的 HBEC 致瘤性的参与者； 4) 利用NFAT和NF(B-荧光素酶转基因小鼠)建立镍化合物对NFAT和NF(B激活的体内影响。本申请提出的研究的意义在于，所提出的研究结果将极大地促进对镍化合物致癌作用的分子机制的理解。本研究还将提供体内模型来进一步研究NFAT和NF(B激活在镍诱发体内癌发生中的作用。此外，它还将帮助我们确定是否可以使用NFAT或NF(B作为化学预防镍诱发癌发生的靶点。