Investigation of Cellular Responses to Genotoxic Stress

描述(申请人提供)：所有生物体的遗传物质均受 每天接二连三的来自环境或由正常细胞新陈代谢产生的物理和化学侮辱。这种遗传毒性物质改变了DNA成分的化学结构，从而改变了它的编码特性，并为随后导致各种潜在有害生物后果的事件奠定了基础，这些后果包括细胞死亡、功能受损、突变，对于人类来说，还会发展成癌症。 这份修订后的计划项目建议书由五个研究项目组成，重点关注细胞对遗传毒性应激的反应，这些应激反应来自代表主要类别的环境相关化学品和辐射的试剂，以及可能在细胞内自发产生的活性氧(ROS)等试剂。在这方面，重点将放在对氧化、烷基化和亚硝化剂以及辐射造成的DNA损伤的反应上。作为工业、农业和生活方式活动的结果，人类和其他生物体暴露在这种制剂中。 在过去的几年里，一大批在DNA损伤和耐药性领域有着共同利益的调查人员聚集在埃默里大学。该计划项目的五名主要研究人员代表了这一临界量的大部分。这些组织有着卓有成效的互动和合作的历史。预计持续的互动以及新合作的发展将进一步协同这些小组的努力，显著推动发现的步伐，并使这些研究人员能够达到新的水平，理解DNA修复、损伤容忍和直接损伤预防途径是如何相互交织在一起的。 酵母菌和细菌模型系统将被用来解决生物体抵抗DNA损伤的引入和影响的策略的几个重要方面。将分析的DNA损伤抵抗策略将包括DNA修复、损伤容忍和直接预防途径。这一修订计划项目的广泛主题是描述在细胞对DNA损伤剂暴露的反应期间在不同水平上运行的系统的相互作用和互补网络的特征。在执行这一计划时，预计研究人员对细胞中DNA损伤处理的理解将提高到一个显著更高的水平。

DESCRIPTION (provided by applicant): The genetic material of all organisms is subject to a daily barrage of physical and chemical insults coming from the environment or produced by normal cellular metabolism. Such genotoxic agents change the chemical structure of the components of DNA and hence its coding properties and set the stage for subsequent events that lead to a variety of potentially deleterious biological consequences including cell death, impaired function, mutation, and in the case of humans, the development of cancer. This revised Program Project proposal is comprised of five research projects focused on the cellular responses to genotoxic stress from agents that are representative of major classes of environmentally relevant chemicals and radiation as well as agents, such as reactive oxygen species, (ROS) which may be generated spontaneously within cells. In this regard, an emphasis will be placed on responses to DNA damage caused by oxidizing, alkylating, and nitrosating agents as well as radiation. Humans and other organisms are exposed to such agents as a consequence of industrial, agricultural and lifestyle activities. Over the past several years, a critical mass of investigators with common interests in the area of DNA damage, resistance have assembled at Emory University. The five principal investigators of this Program Project represent a majority of this critical mass. These groups have a history of productive interactions and collaborations. It is anticipated that continued interactions as well as the development of new collaborations will further synergize the efforts of the groups, propelling the pace of discovery significantly and allow these investigators to reach new levels of comprehension of how DNA repair, damage tolerance, and direct damage prevention pathways are intertwined. Yeast and bacterial model systems will be employed to address several important aspects of strategies employed by organisms to resist the introduction and effects of DNA damage. The DNA damage resistance strategies that will be analyzed will include DNA repair, damage tolerance and direct prevention pathways. The broad theme of this revised Program Project is the characterization of the interacting and complementary networks of systems that operate at different levels during the cellular response to exposures to DNA damaging agents. In pursuing this Program, it is anticipated that the investigators' understanding of DNA damage processing in cells will be brought to a significantly higher level of resolution.