New Reagents for Tracking Protein Oxidation in Cells by MS and Imaging Methods
通过质谱和成像方法追踪细胞中蛋白质氧化的新试剂
基本信息
- 批准号:8547235
- 负责人:
- 金额:$ 34.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The association of reactive oxygen species (ROS) with the initiation and progression of cancer, including stimulation of tumor growth and metastasis, is well established; paradoxically, ROS are also important players in many anti-cancer treatments involving ionizing radiation and chemotherapies. Yet we have only a limited appreciation for the molecular mechanisms involved in the many normal and disease-associated functional roles played by ROS, largely due to the limited tools available for studying the molecular targets of ROS. Our research team at Wake Forest University has pioneered the development of highly specific chemical probes, with previous support from the IMAT program, which enable detection and identification of oxidized proteins, targeting the initial sulfenic acid(-SOH) product of cysteine thiols undergoing oxidation. While these probes have been used successfully to identify targets of oxidation within specific proteins such as Akt2 (in the context
of PDGF signaling) and specific lipid raft-associated protein tyrosine phosphatases involved in angiogenesis, they have not yet proven amenable to wide-scale identification of such sites using high- throughput mass spectrometry (MS) analysis. As demonstrated in our preliminary data, factors which interfere with MS have been identified and circumvented with new probe designs; for example, acid-base properties of these 1,3-dicarbonyl probes which interfere with the charge states needed for MS detection can be blocked by post-labeling cyclization of the products, and new linear probes exhibiting much higher reactivity with the low abundance sulfenic acids have been generated. This application describes additional new strategies to overcome the remaining issues that limit detection and analysis of the oxidized proteome. The first aim describes new chemical probes for more efficient trapping of electrophilic and nucleophilic sulfenic acids. With the second aim we will investigate new imaging and MS technologies to visualize selective protein -SOH modification in situ and identify sulfenic acid sites in endogenously expressed proteins. Successful completion of this project will have high impact, enabling a much deeper understanding of redox-controlled intracellular processes involved in normal and cancer signaling, angiogenesis and metastasis, as well as chemotherapeutic and radiation-based treatments. In the long term, it may enable the design of selective agonists or antagonists to modulate the activity of target proteins in tumors.
描述(由申请人提供):充分性氧(ROS)与癌症的起始和进展(包括肿瘤生长和转移的刺激)的结合;矛盾的是,ROS在许多涉及电离辐射和化学疗法的抗癌治疗中也是重要的参与者。然而,我们对ROS扮演的许多正常和疾病相关的功能作用的分子机制的欣赏仅有限,这在很大程度上是由于可用于研究ROS的分子靶标的有限的工具。在IMAT计划的先前支持下,Wake Forest University的研究团队率先开发了高度特异性的化学探针,该探测器可以检测和鉴定氧化蛋白质,以氧化氧化的初始硫酸(-SOH)乘积。尽管这些探针已成功地用于识别特定蛋白质(例如Akt2)内的氧化靶
PDGF信号传导)和参与血管生成的特定脂质筏相关蛋白酪氨酸磷酸酶,它们尚未证明使用高吞吐量质谱法(MS)分析可与此类部位的广泛鉴定。正如我们的初步数据所示,干扰MS的因素已被鉴定出来并通过新的探针设计进行了规避。例如,这些1,3-二碳苯子探针的酸碱特性可以通过产物的标记后环化来阻断MS检测所需的电荷状态,并且已经产生了新的线性探针与低丰度硫化硫酸的新线性探针已被产生。该应用程序描述了克服限制氧化蛋白质组检测和分析的其余问题的其他新策略。第一个目的描述了新的化学探针,以更有效地捕获亲电和亲核硫酸。以第二个目的,我们将研究新的成像和MS技术,以可视化选择性蛋白质-SOH原位修饰,并在内源表达的蛋白质中鉴定硫酸位点。该项目的成功完成将产生很大的影响,从而使人们对参与正常和癌症信号,血管生成和转移的氧化还原控制的细胞内过程以及化学治疗和基于辐射的治疗。从长远来看,它可以使选择性激动剂或拮抗剂的设计能够调节肿瘤中靶蛋白的活性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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数据更新时间:2024-06-01
Cristina Maria Fur...的其他基金
Redox Biology and Medicine Training Program
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- 批准号:1064147710641477
- 财政年份:2023
- 资助金额:$ 34.21万$ 34.21万
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Overcoming racial health disparities in lung cancer through innovative mechanism-based therapeutic strategies
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Redox Biology and Medicine Training Program
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- 批准号:1020083910200839
- 财政年份:2018
- 资助金额:$ 34.21万$ 34.21万
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Model-based Prediction of Redox-Modulated Responses to Cancer Treatments
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- 批准号:97696999769699
- 财政年份:2017
- 资助金额:$ 34.21万$ 34.21万
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New Oxidation-Sensing Probes to Evaluate Mitochondrial Dysfunction in Lung Injury
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- 批准号:95137749513774
- 财政年份:2017
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Model-based Prediction of Redox-Modulated Responses to Cancer Treatments
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- 批准号:1024707410247074
- 财政年份:2017
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New Oxidation-Sensing Probes to Evaluate Mitochondrial Dysfunction in Lung Injury
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2014 Thiol-based Redox Regulation & Signaling GRC and GRS
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- 资助金额:$ 34.21万$ 34.21万
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New Reagents for Tracking Protein Oxidation in Cells by MS and Imaging Methods
通过质谱和成像方法追踪细胞中蛋白质氧化的新试剂
- 批准号:87218988721898
- 财政年份:2013
- 资助金额:$ 34.21万$ 34.21万
- 项目类别:
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