Cellular Responses to Localized Oxidative Stress

活性氧化物质（ROS）由许多用于治疗癌症的试剂产生，例如，电离辐射、光动力疗法和一些化疗药物。ROS介导的过程也通过启动和参与导致有丝分裂和肿瘤促进的信号级联反应以及通过引起突变在肿瘤发展中发挥关键作用。另一方面，ROS对一些正常的生理过程也至关重要。本计划项目资助申请解决的中心问题是：活性氧化物质如何启动如此多样的细胞反应？不是所有的ROS都是平等的。它们引发的细胞反应取决于ROS类型（以及因此的反应性）、ROS产生的亚细胞位点、ROS浓度以及从ROS产生位点到反应位点的信号传递模式。在这个修订的程序中，我们将分析ROS对细胞毒性和细胞毒性的影响。 信号传导（项目1）、凋亡（项目2）和DNA损伤诱导和诱变（项目3）。预计ROS的类型（1O2、.OH或H2O2）及其形成部位会影响所有这些反应。通过初始ROS本身、次级ROS、ROS产物或由ROS引发的生物分子变化级联的扩散的细胞信号传导将被解决。核心A将提供最先进的设施和专业知识，这些设施和专业知识对于使用激光和光敏剂进行ROS亚细胞生产、监测ROS以及细胞成像和分析的所有项目都是不可或缺的。格雷癌症研究所提供电离辐射微束，能够将空间分辨的电离辐射传递到单个细胞或亚细胞区域。拟议的PPG汇集了一支由经验丰富的调查人员组成的高度互动的跨学科团队，他们使用复杂的工具来解决以下基本问题： 了解氧化应激的分子机制，因为它与癌症的发展和治疗有关。预计这将导致增加的洞察力，最终将通过转化为预防或治疗癌症的改进方法来满足迫切的需求。

Reactive oxidizing species (ROS) are produced by many agents used in the treatment of cancer, e.g., ionizing radiation, photodynamic therapy and some chemotherapy drugs. ROS-mediated processes also play critical roles in tumor development by initiating and participating in signaling cascades leading to mitogenesis and tumor promotion, and by causing mutations. On the other hand, ROS are also vital to some normal physiological processes. The central question addressed by this Program Project Grant application is: How do reactive oxidizing species initiate such diverse cellular responses? Not all ROS are created equal. The cellular responses they initiate depend on ROS type (and hence reactivity), subcellular site of ROS generation, ROS concentration, and mode of signal transmission from the site of ROS generation to the site of response. In this revised Program, we will analyze the effects of ROS on cytotoxicity and cell signaling (Project 1 ), apoptosis (Project 2), and DNA damage induction and mutagenesis (Project 3). The type of ROS (1O2, .OH or H2O2) and its site of formation are expected to affect all these responses. Cellular signaling by diffusion of the initial ROS itself, secondary ROS, products of the ROS, or cascades of biomolecular changes initiated by ROS will be addressed. Core A will provide state-of-the-art facilities and expertise that are indispensable for all projects for subcellular production of ROS using laser light and photoactive agents, monitoring ROS, and cell imaging and analysis. The Gray Cancer Institute provides the ionizing radiation microbeams, capable of delivering spatially-resolved ionizing radiation to individual cells or subcellular regions. The proposed PPG has brought together a highly interactive, interdisciplinary team of experienced investigators using sophisticated tools to address questions that are fundamental to understanding molecular mechanisms of oxidative stress as it relates to cancer development and treatment. This is expected to result in increased insight that ultimately will fill an urgent need by translating into improved methods to prevent or treat cancer.