Mechanisms of As-Induced Carcinogenesis

描述（由申请人提供）：由于砷的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首要环境问题。流行病学研究提供了充分的证据表明，砷暴露与皮肤癌和肺癌发病率的增加有关。母公司资助的范围解决了活性氧（ROS）的产生和皮肤致癌的关系，由于砷暴露在人类角质形成细胞和小鼠皮肤模型。虽然目前的竞争性修订的范围旨在评估亚砷酸盐诱导的慢性炎症与体外和体内肺癌发生之间联系的贡献和分子机制，但这一竞争性修订旨在扩大最初的研究范围，从ROS生成介导皮肤癌发生，来确定亚砷酸盐的分子机制在体外和体内细胞以及动物对砷暴露的反应中诱导慢性炎症至肺致瘤性。虽然母基金和当前的竞争性修订都建议研究砷暴露致癌作用的机制，但本修订特别旨在确定关键炎症介质TNF-1和考克斯-2对砷诱导的体外和体内人支气管上皮细胞（HBEC）致瘤性发展的贡献，以及在这个肿瘤发生过程中涉及的分子机制。本修订的主要假设是TNF-1在持续慢性肺部炎症的形成和维持中起核心作用，随后导致砷暴露诱导肺上皮细胞致瘤性。本研究的总体目标是确定TNF-1和考克斯-2在砷诱导的HBEC致瘤性中的作用，以及TNF-1在体外和体内砷暴露期间维持肺慢性炎症中的核心作用。本研究有两个具体目的：1）确定TNF-1和考克斯-2对砷暴露引起的HBEC致瘤性发展的贡献; 2）评估TNF-1在砷诱导的肺慢性炎症中的中心作用及其体内机制。该修订的成功将有助于我们理解慢性肺部炎症微环境形成和维持的分子机制，以及其在砷暴露诱导的肺癌发生中的作用。对这些问题的更好理解可能为设计更有效的预防和治疗炎症相关肺癌的药物提供有价值的信息。此外，本次竞争性修订的资金将节省两个工作，一个是Jianxiu Yu博士的兼职工作，另一个是Dongyun Zhang，他们都提供了宝贵的专业知识，对拟议的研究至关重要。这一发现还将为两名博士后研究员在拟议的研究领域创造新的培训机会。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或商业上获得，我们相信拟议的研究将在两年内实现。 公共卫生相关性：砷在美国和世界范围内仍然是首要的环境问题，并且持续的肺部慢性炎症微环境的存在被认为是由于砷暴露导致肺癌发展的主要驱动力，然而，将砷暴露与肺部慢性炎症联系起来的分子机制是完全未知的。本申请是为了测试的假设，TNF-1起着核心作用，在形成和维持持续的慢性肺部炎症和诱导肺上皮细胞致瘤性由于砷暴露。该修订的成功将有助于我们理解肺慢性炎症微环境形成和维持的分子机制，以及其在砷暴露诱导的肺癌发生中的作用。更好地理解这些问题可能会提供有价值的信息，设计更有效的药物预防和治疗炎症相关的肺癌。

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.