Proteomic Profiling of Cancer-Related Redox Signaling Pathways

癌症相关氧化还原信号通路的蛋白质组学分析

基本信息

  • 批准号:
    7790611
  • 负责人:
  • 金额:
    $ 26.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-05-01 至 2012-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): It is widely appreciated that reactive oxygen species (ROS) play a major role in the initiation of cancer, and they are also implicated in many cancer therapies, such as ionizing radiation, cisplatin and taxanes. More recently, it has been discovered that cancer cells produce ROS as signaling molecules that promote proliferation. Unfortunately, the molecular details of how redox regulation affects cell signaling events are far from clear. New experimental and computational technologies that we have developed are uniquely suited to identifying the molecular targets that are modified by ROS, either as a result of ROS damage or ROS signaling. With the reagents and methods that we have recently developed, we can now evaluate the "redox profile" of cell populations by targeting uniquely reactive cysteine sulfenic acid (Cys-SOH) groups, the initial intermediates generated following reaction of activated protein thiolate groups with hydrogen peroxide and peroxynitrite (and perhaps other ROS). In this R33 application, our labeling technology will be further developed for quantification and multiplex analysis, so that it will have broad applicability in: 1) the investigation of basic mechanisms of ROS damage and ROS signaling; 2) molecular profiling to stratify patients with cancers that are sensitive to ROS-generating therapies; and 3) the development of novel cancer therapies based on the inhibition of ROS-dependent proliferative signaling. The following Specific Aims are proposed: 1) to develop reagents and methods of use for additional new, multicolor fluorescently-labeled Cys-SOH reagents for multiplex analysis of samples; 2) to develop quantitative mass spectrometry methods, which have some major advantages over gel-based methods (including direct readout of protein identity and numerous posttranslational modifications); and 3) to use the new quantitative methods to detect and identify Cys-SOH modified proteins generated during ROS-dependent signaling in HEK-293 cells and ovarian cancer cells. Taken together, the approaches developed in Specific Aims 1 and 2 will provide new tools for the research community to use to study the mechanisms of redox regulation and signaling. In Specific Aim 3, these tools will be used to determine the targets of ROS in the regulation of cell proliferation and apoptosis. First we will continue our study of NF-?B regulation in HEK-293 cells in response to cytokine (TNF-?) and tumor promoter (TPA) stimulation. Second, we will use ovarian cancer cells treated with cisplatin or taxane to determine which protein oxidations are critical to regulating survival and apoptosis. Besides providing specific information about the mechanism of redox regulation and signaling, these biological experiments will allow us to further refine our reagents and methods to make them most useful to the cancer biology community. These approaches to detecting functional oxidative modifications to cellular proteins hold promise in identifying specific protein targets that mediate the actions of anticancer drugs, e.g. through their effects on cell cycle arrest, cell division or apoptosis. An outgrowth of these studies could also be the development of new anticancer drugs and the ability to predict efficacy of a given drug in the treatment of individual patients.
描述(由申请人提供):广泛理解的是,活性氧(ROS)在癌症的启动中起主要作用,并且还与许多癌症疗法有关,例如电离辐射,顺铂,顺铂和紫杉烷。最近,已经发现,癌细胞将ROS作为促进增殖的信号分子。不幸的是,氧化还原调控如何影响细胞信号事件的分子细节远非清晰。我们开发的新实验和计算技术非常适合识别由ROS损伤或ROS信号导致ROS修饰的分子靶标。借助我们最近开发的试剂和方法,我们现在可以通过靶向独特的活性半胱氨酸硫酸(CYS-SOH)组来评估细胞群体的“氧化还原谱”,在激活的蛋白质硫代基团与过氧化物过氧化物和氧化物氧化物和氧基硝酸盐的反应后,产生的初始中间体生成的初始中间体产生。在此R33应用中,我们的标签技术将进一步开发用于量化和多重分析,以便在以下方面具有广泛的适用性:1)研究ROS损伤和ROS信号传导的基本机制; 2)分子分析以分层对产生ROS的疗法敏感的癌症患者; 3)基于抑制ROS依赖性增殖信号传导的新型癌症疗法的发展。提出了以下具体目的:1)开发用于其他新的多色荧光标记的Cys-SOH试剂的试剂和使用方法,用于样品的多重分析; 2)开发定量质谱法,这些方法比基于凝胶的方法具有一些主要优势(包括直接读数蛋白质身份和众多翻译后修饰); 3)使用新的定量方法检测和鉴定在HEK-293细胞和卵巢癌细胞中ROS依赖性信号传导过程中产生的Cys-SOH修饰蛋白。综上所述,特定目标1和2中开发的方法将为研究社区提供新的工具,以研究氧化还原调节和信号传导的机制。在特定的目标3中,这些工具将用于确定ROS在细胞增殖和凋亡调节中的靶标。首先,我们将继续研究HEK-293细胞中的NF-?B调节,以响应细胞因子(TNF-?)和肿瘤启动子(TPA)刺激。其次,我们将使用用顺铂或紫杉烷处理的卵巢癌细胞来确定哪些蛋白质氧化对于调节生存和凋亡至关重要。除了提供有关氧化还原调节和信号传导机制的特定信息外,这些生物学实验还将使我们能够进一步完善我们的试剂和方法,使其对癌症生物学界最有用。这些检测对细胞蛋白的功能氧化修饰的方法在识别介导抗癌药物作用的特定蛋白靶标方面有望,例如通过对细胞周期停滞,细胞分裂或凋亡的影响。这些研究的产物也可能是新抗癌药的发展,以及预测给定药物在治疗个别患者中的功效的能力。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Simple synthesis of 1,3-cyclopentanedione derived probes for labeling sulfenic acid proteins.
A simple and effective strategy for labeling cysteine sulfenic acid in proteins by utilization of β-ketoesters as cleavable probes.
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LESLIE B POOLE其他文献

LESLIE B POOLE的其他文献

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{{ truncateString('LESLIE B POOLE', 18)}}的其他基金

Redox Regulation of Cysteine-Dependent Peroxidases and Signal Transduction Pathways
半胱氨酸依赖性过氧化物酶和信号转导途径的氧化还原调节
  • 批准号:
    10548745
  • 财政年份:
    2020
  • 资助金额:
    $ 26.05万
  • 项目类别:
Mechanisms and Regulation of Peroxiredoxins
过氧化还原蛋白的机制和调控
  • 批准号:
    9121765
  • 财政年份:
    2016
  • 资助金额:
    $ 26.05万
  • 项目类别:
2012 Thiol-based Redox Regulation & Signaling GRC and GRS
2012年硫醇基氧化还原调节
  • 批准号:
    8252744
  • 财政年份:
    2011
  • 资助金额:
    $ 26.05万
  • 项目类别:
2010 Thiol-based Redox Regulation & Signaling Gordon Research Conference
2010年硫醇基氧化还原法规
  • 批准号:
    7804202
  • 财政年份:
    2010
  • 资助金额:
    $ 26.05万
  • 项目类别:
Proteomic Profiling of Cancer-Related Redox Signaling Pathways
癌症相关氧化还原信号通路的蛋白质组学分析
  • 批准号:
    7366882
  • 财政年份:
    2008
  • 资助金额:
    $ 26.05万
  • 项目类别:
Proteomic Profiling of Cancer-Related Redox Signaling Pathways
癌症相关氧化还原信号通路的蛋白质组学分析
  • 批准号:
    7618024
  • 财政年份:
    2008
  • 资助金额:
    $ 26.05万
  • 项目类别:
Proteomic Profiling of Cancer-Related Redox Signaling Pathways
癌症相关氧化还原信号通路的蛋白质组学分析
  • 批准号:
    7908083
  • 财政年份:
    2008
  • 资助金额:
    $ 26.05万
  • 项目类别:
Proteomic Profiling of Cancer-Related Redox Signaling Pathways
癌症相关氧化还原信号通路的蛋白质组学分析
  • 批准号:
    7918510
  • 财政年份:
    2008
  • 资助金额:
    $ 26.05万
  • 项目类别:
Profiling of Redox-Sensitive Signaling Proteins
氧化还原敏感信号蛋白的分析
  • 批准号:
    7060447
  • 财政年份:
    2005
  • 资助金额:
    $ 26.05万
  • 项目类别:
Profiling of Redox-Sensitive Signaling Proteins
氧化还原敏感信号蛋白的分析
  • 批准号:
    6861333
  • 财政年份:
    2005
  • 资助金额:
    $ 26.05万
  • 项目类别:

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