Mechanisms of As-Induced Carcinogenesis

砷诱发的致癌机制

• 批准号: 7844264
• 负责人: CHUANSHU HUANG
• 金额: $ 66.35万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844264
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Address; Alkaline Phosphatase; Animal Experimentation; Animals; Arsenic; Arsenites; Cell Line; Cells; Chronic; Cyclic AMP-Dependent Protein Kinases; Cytomegalovirus; Data; Development; EGF gene; Electron Spin Resonance Spectroscopy; Embryo; Epidemiologic Studies; Epidermal Growth Factor; Epithelial Cells; Exposure to; Feedback; Fibroblasts; Figs - dietary; Funding; Generations; Glycogen Synthase Kinase 3; Goals; Grant; Health; Human; Immunoglobulin G; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; International Agency for Research on Cancer; Investigation; Laboratories; Link; Lipids; Lung; Lung Inflammation; MAP Kinase Gene; MAPK8 gene; MEKs; Maintenance; Malignant neoplasm of lung; Mediating; Mediation; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Nuclear; Occupations; PTGS2 gene; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Play; Postdoctoral Fellow; Prevention therapy; Process; Protein Kinase; ROS1 gene; Reactive Oxygen Species; Research; Role; Signal Transduction; Skin; Skin Carcinogenesis; Small Interfering RNA; Superoxide Dismutase; T-Cell Activation; T-Lymphocyte; Testing; Time; Training; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumorigenicity; United States; base; carcinogenesis; cyclooxygenase 2; design; driving force; extracellular; fetal bovine serum; in vivo; inhibitor/antagonist; keratinocyte; lung carcinogenesis; nuclear factors of activated T-cells; parent grant; platelet protein P47; public health relevance; response; stress-activated protein kinase 1; success; tool; tumorigenic

DESCRIPTION (provided by applicant): Arsenic remains a top environmental concern in the United States as well as world-wide because of its global existence and serious health impacts. Epidemiological studies provide ample evidence that arsenite exposure is associated with the increased incidence of skin and lung cancers. The scope of the parent grant addresses the relation of reactive oxygen species (ROS) generation and skin carcinogenesis due to arsenite exposure in both the human keratinocytes and the mouse skin models. While the scope of current competitive revision seeks to evaluate the contribution and molecular mechanisms of linking the arsenite-induced chronic inflammation to lung carcinogenesis both in vitro and in vivo, this competitive revision seeks to expand the original scope of study from ROS generation in the mediation of skin carcinogenesis, to identification of the molecular mechanisms that link arsenite-induced chronic inflammation to lung tumorigenicity in vitro and in vivo in cellular as well as animal response to arsenite exposure. Although both the parent grant and the current competitive revision propose to study the mechanisms implicated in the carcinogenic effects of arsenite exposure, this revision is specifically intended to identify the contribution of key inflammatory mediators TNF-1 and COX-2 to arsenite-induced development of tumorigenicity of human bronchial epithelial cells (HBECs) in vitro and in vivo, as well as the molecular mechanisms involved in this tumorigenic process. The main hypothesis of this revision is that TNF-1 plays a central role in the formation and maintenance of sustained chronic lung inflammation and subsequently results in the induction of lung epithelial cell tumorigenicity due to arsenic exposure. The overall goal of this proposal is to determine role of TNF-1 and COX-2 in arsenite-induced HBECs' tumorigenicity, as well as the central role of TNF-1 in the maintenance of lung chronic inflammation during arsenic exposure both in vitro and in vivo. There are two Specific Aims proposed for this investigation: 1) To determine the contribution of TNF-1 and COX-2 to the development of tumorigenicity of HBECs due to arsenic exposure; 2) To assess the central role of TNF-1 in arsenic-induced lung chronic inflammation and its mechanisms in vivo. Success of the revision will facilitate our understanding of the molecular mechanism(s) of the formation and maintenance of the chronic lung inflammatory microenvironment, and its role in lung cancer development induced by arsenic exposure. A better understanding of those issues may provide valuable information that is needed for the designing more effective agents for the prevention of and therapy for inflammation-associated lung cancers. Furthermore, funding of this competitive revision will save two jobs, one part-time for Dr. Jianxiu Yu and one for Dongyun Zhang, both of whom provide valuable expertise and are crucial for the proposed studies. The finding will also create new training opportunity for two postdoctoral fellows in the proposed research field. Since we have most of research tools, and research animals are either available in our laboratory or commercially, we believe that the proposed studies will be achieved within two years. PUBLIC HEALTH RELEVANCE: Arsenic remains the top environmental concern in United States as well as world wide, and the existence of a sustained lung chronic inflammatory microenvironment is thought to be a major driving force for the development of lung cancers due to arsenite exposure, however, the molecular mechanisms linking arsenite exposure to lung chronic inflammation are totally unknown. This application is to test the hypothesis that TNF-1 plays a central role in the formation and maintenance of sustained chronic lung inflammation and induction of lung epithelial cell tumorigenicity due to arsenic exposure. Success of the revision will facilitate our understanding of the molecular mechanism(s) of the formation and maintenance of the lung chronic inflammatory microenvironment, and its role in lung cancer development induced by arsenic exposure. A better understanding of those issues may provide valuable information needed for designing more effective agents for prevention and therapy of the inflammation-associated lung cancers.

描述（由申请人提供）：由于其全球存在和严重的健康影响，砷仍然是美国和世界范围内的最大环境关注。流行病学研究提供了充分的证据，表明砷暴露与皮肤和肺癌的发生率增加有关。父授予的范围解决了人角质形成细胞和小鼠皮肤模型的砷暴露而导致的活性氧（ROS）产生和皮肤致癌的关系。虽然当前竞争性修订的范围旨在评估将砷引起的慢性炎症与肺癌发生连接到体外和体内肺癌发生的贡献和分子机制，但这种竞争性的修订旨在扩大研究的原始研究范围，从ROS的产生范围从ROS的产生到识别的介于皮肤的介导，并将其识别为识别。体外和体内肿瘤性在细胞中以及动物对砷暴露的反应。 Although both the parent grant and the current competitive revision propose to study the mechanisms implicated in the carcinogenic effects of arsenite exposure, this revision is specifically intended to identify the contribution of key inflammatory mediators TNF-1 and COX-2 to arsenite-induced development of tumorigenicity of human bronchial epithelial cells (HBECs) in vitro and in vivo, as well as the molecular这种致瘤过程涉及的机制。这项修订的主要假设是，TNF-1在持续的慢性肺部炎症的形成和维持中起着核心作用，随后导致由于砷暴露而导致肺上皮细胞肿瘤性诱导。该提案的总体目的是确定TNF-1和COX-2在砷诱导的HBEC肿瘤性中的作用，以及TNF-1在体外和体内砷暴露期间TNF-1在维持肺部慢性炎症过程中的核心作用。这项研究提出了两个具体的目的：1）确定TNF-1和COX-2对由于砷暴露而导致HBEC肿瘤性的发展的贡献； 2）评估TNF-1在砷诱导的肺慢性炎症及其在体内的机制中的核心作用。修订的成功将有助于我们理解慢性肺炎性微环境的形成和维持的分子机制，以及其在砷暴露引起的肺癌发育中的作用。更好地理解这些问题可能会提供有价值的信息，以设计更有效的药物预防和治疗与炎症相关的肺癌。此外，这种竞争性修订的资金将节省两个工作，为Jianxiu Yu博士兼职，一项为Dongyun Zhang提供了兼职，他们俩都提供了宝贵的专业知识，对于拟议的研究至关重要。这一发现还将为拟议的研究领域的两个博士后研究员创造新的培训机会。由于我们拥有大多数研究工具，并且研究动物可以在我们的实验室中或商业上可用，因此我们认为拟议的研究将在两年内实现。 公共卫生相关性：砷仍然是美国和世界范围内的首要环境关注，并且存在持续的肺慢性炎症微环境被认为是由于砷暴露而导致肺癌导致肺癌的主要驱动力，但是由于分子机制与肺炎炎症相关的分子机制是将砷暴露联系到肺部慢性慢性疾病的完全驱动力。该应用是为了检验以下假设：TNF-1在持续的慢性肺部炎症和诱导肺部细胞肿瘤性诱导症引起的肺部炎症和诱导诱导砷导致的肺部炎症中起着核心作用。修订的成功将有助于我们理解肺部慢性炎症微环境的形成和维持的分子机制，以及其在砷暴露引起的肺癌发育中的作用。对这些问题的更好理解可能会为设计更有效的药物预防和治疗与炎症相关的肺癌所需的有价值的信息。