New Oxidation-Sensing Probes to Evaluate Mitochondrial Dysfunction in Lung Injury
用于评估肺损伤中线粒体功能障碍的新型氧化传感探针
基本信息
- 批准号:9513774
- 负责人:
- 金额:$ 51.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-14 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Mitochondrial dysfunction and accumulation of reactive oxygen species (ROS) in environmentally associated diseases is well established. Yet we have only a limited appreciation for the molecular mechanisms linking these processes to changes in cellular phenotype underlining the pathogenesis of environmental stressors. With previous support from the NIH IMAT program, this research team at Wake Forest has pioneered the development of highly specific chemical probes, which enable detection and identification of oxidized proteins (molecular targets of ROS). While these probes have been used successfully to identify global targets of oxidation within cellular proteins under numerous disease conditions (e.g., cancer, aging, inflammation), they have not yet been targeted to specific organelles within the cells or applied to study cellular response to environmental stressors. The current proposal describes new strategies to achieve these important tasks by focusing first (R21 phase) on the development and validation of mitochondria-targeted chemical probes for protein oxidation and then (R33 phase) on the application of these oxidation-sensing probes and methods of analysis to investigate mechanisms of lung Injury induced by ionizing radiation(IR) and silver nanoparticles (AgNP). The new probes will enable selective labeling of electrophilic and nucleophilic protein sulfenic acids (-SOH) in mitochondria. New imaging methods that combine the mitochondria-targeted and oxidation-sensing probes with an antibody against the protein of interest will be employed to visualize selective protein -SOH modification in situ and movement of the oxidized protein within the cell (e.g., between mitochondria and nucleus). The probes will then be employed mechanistically to investigate the relationship between mitochondrial dysfunction and environmental lung injury. New computational methods (COSMro) will be employed to infer mitochondria-dependent up or downregulation of specific pathways, which will then be validated using studies in cells and animal models of lung injury. These studies will be performed in young and old animals using single and combined environmental stressors to mimic to the extent possible the environmental exposure in a human population. Successful completion of this project will have high impact, enabling a much deeper understanding of mitochondria- and redox-controlled intracellular processes involved in the biological response to environmental stressors encountered in our daily lives.
描述(由应用提供):已建立了线粒体功能障碍和活性氧(ROS)在环境相关疾病中的积累。然而,我们对将这些过程与强调环境应激源发病机理的变化的分子机制相关的分子机制有限。在NIH IMAT计划的先前支持下,Wake Forest的该研究团队率先开发了高度特异性的化学问题,这可以检测和鉴定氧化蛋白(ROS的分子靶标)。尽管这些问题已成功地用于鉴定在许多疾病条件下(例如癌症,衰老,炎症)中细胞蛋白质中的全球氧化靶标,但它们尚未针对细胞内的特定细胞器或用于研究对环境压力源的细胞反应。当前的建议描述了通过将第一(R21阶段)集中在蛋白质氧化的线粒体靶向化学问题的开发和验证上,以实现这些重要任务的新策略,然后(R33阶段)(R33阶段)应用这些氧化问题和分析方法的应用,以及分析方法来调查导致辐射辐射辐射(IRiation radiation(IRIADIAL)(IRIADIEN)(IRIAD)(IR)(IR)和Silver Silver nanapicles(Agriation)(Agriation)(Agriation)。新的探针将使线粒体中的亲电和核纤维蛋白硫酸(-SOH)选择性标记。将使用针对线粒体靶向的新成像方法与针对感兴趣蛋白质的抗体结合使用,以可视化细胞内氧化蛋白的原位选择性蛋白质-SOH修饰和运动(例如,线粒体和核之间)。然后,这些问题将被机械地研究线粒体功能障碍与环境肺损伤之间的关系。将采用新的计算方法(COSMRO)来推断特定途径的线粒体依赖性或下调,然后使用在肺损伤细胞和动物模型中进行研究来验证。这些研究将使用单一和联合环境压力源在年轻和老年动物中进行,以模仿人口的环境暴露。该项目的成功完成将产生很大的影响,从而使对我们日常生活中遇到的环境压力源的生物反应涉及的线粒体和氧化还原控制的细胞内过程有更深入的了解。
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
氧化还原生物学与医学培训计划
- 批准号:1064147710641477
- 财政年份:2023
- 资助金额:$ 51.63万$ 51.63万
- 项目类别:
Overcoming racial health disparities in lung cancer through innovative mechanism-based therapeutic strategies
通过基于机制的创新治疗策略克服肺癌的种族健康差异
- 批准号:1066029410660294
- 财政年份:2023
- 资助金额:$ 51.63万$ 51.63万
- 项目类别:
Redox Biology and Medicine Training Program
氧化还原生物学与医学培训计划
- 批准号:1043979410439794
- 财政年份:2018
- 资助金额:$ 51.63万$ 51.63万
- 项目类别:
Redox Biology and Medicine Training Program
氧化还原生物学与医学培训计划
- 批准号:1020083910200839
- 财政年份:2018
- 资助金额:$ 51.63万$ 51.63万
- 项目类别:
Model-based Prediction of Redox-Modulated Responses to Cancer Treatments
基于模型的氧化还原调节对癌症治疗反应的预测
- 批准号:97696999769699
- 财政年份:2017
- 资助金额:$ 51.63万$ 51.63万
- 项目类别:
Model-based Prediction of Redox-Modulated Responses to Cancer Treatments
基于模型的氧化还原调节对癌症治疗反应的预测
- 批准号:1024707410247074
- 财政年份:2017
- 资助金额:$ 51.63万$ 51.63万
- 项目类别:
New Oxidation-Sensing Probes to Evaluate Mitochondrial Dysfunction in Lung Injury
用于评估肺损伤中线粒体功能障碍的新型氧化传感探针
- 批准号:89278448927844
- 财政年份:2015
- 资助金额:$ 51.63万$ 51.63万
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2014 Thiol-based Redox Regulation & Signaling GRC and GRS
2014年硫醇氧化还原法规
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- 财政年份:2014
- 资助金额:$ 51.63万$ 51.63万
- 项目类别:
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:$ 51.63万$ 51.63万
- 项目类别:
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:85472358547235
- 财政年份:2013
- 资助金额:$ 51.63万$ 51.63万
- 项目类别:
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