Cellular Responses to Localized Oxidative Stress

细胞对局部氧化应激的反应

基本信息

批准号：
7268863
负责人：
Kathryn Dale Held
金额：
$ 119.35万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268863
关键词：
Cellular Responses Localized Oxidative Stress

项目摘要

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.

活性氧化物质（ROS）是由许多用于治疗癌症的药物产生的，例如电离辐射、光动力疗法和一些化疗药物。 ROS 介导的过程还通过启动和参与导致有丝分裂和肿瘤促进的信号级联以及引起突变，在肿瘤发展中发挥关键作用。另一方面，ROS对于一些正常的生理过程也至关重要。该计划项目拨款申请解决的核心问题是：活性氧化物质如何引发如此多样化的细胞反应？并非所有 ROS 都是一样的。它们引发的细胞反应取决于 ROS 类型（以及反应性）、ROS 生成的亚细胞位点、ROS 浓度以及从 ROS 生成位点到响应位点的信号传输模式。在这个修订后的计划中，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）、细胞凋亡（项目 2）以及 DNA 损伤诱导和诱变（项目 3）。 ROS 的类型（1O2、.OH 或 H2O2）及其形成位点预计会影响所有这些反应。通过初始 ROS 本身、次级 ROS、ROS 产物或 ROS 引发的生物分子变化级联的扩散所产生的细胞信号传导将得到解决。 Core A 将提供最先进的设施和专业知识，这对于使用激光和光活性剂进行 ROS 亚细胞生产、ROS 监测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研究人员组成的高度互动、跨学科的团队，他们使用先进的工具来解决对以下问题至关重要的问题：了解氧化应激与癌症发展和治疗相关的分子机制。预计这将带来更多的见解，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。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biomarkers and mechanisms of FANCD2 function.

DOI：
10.1155/2008/821529
发表时间：
2008
期刊：
Journal of biomedicine & biotechnology
影响因子：
0
作者：
Willers H;Kachnic LA;Luo CM;Li L;Purschke M;Borgmann K;Held KD;Powell SN
通讯作者：
Powell SN

Radiation-induced bystander signalling in cancer therapy.

DOI：
10.1038/nrc2603
发表时间：
2009-05
期刊：
Nature reviews. Cancer
影响因子：
0
作者：
通讯作者：

Introduction to clinical radiation biology.

临床放射生物学简介。

DOI：
10.1016/j.hoc.2006.01.007
发表时间：
2006
期刊：
Hematology/oncology clinics of North America
影响因子：
0
作者：
Willers,Henning;Held,KathrynD
通讯作者：
Held,KathrynD

New molecular targets in radiotherapy: DNA damage signalling and repair in targeted and non-targeted cells.

DOI：
10.1016/j.ejphar.2009.09.068
发表时间：
2009-12-25
期刊：
EUROPEAN JOURNAL OF PHARMACOLOGY
影响因子：
5
作者：
Burdak-Rothkamm, Susanne;Prise, Kevin M.
通讯作者：
Prise, Kevin M.

Ionizing radiation-induced bystander mutagenesis and adaptation: quantitative and temporal aspects.

DOI：
10.1016/j.mrfmmm.2009.08.006
发表时间：
2009-12-01
期刊：
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
影响因子：
2.3
作者：
Zhang, Ying;Zhou, Junqing;Baldwin, Joseph;Held, Kathryn D.;Prise, Kevin M.;Redmond, Robert W.;Liber, Howard L.
通讯作者：
Liber, Howard L.