INDUCIBLE MOUSE MODELS OF MITOCHONDRIAL ROS SIGNALING AND ENVIRONMENTAL STRESS

 描述（由申请人提供）：线粒体是控制代谢的重要多功能细胞器，但也是环境应激的靶点，并参与人类疾病病理学。线粒体产生活性氧（ROS），破坏大分子，促进氧化应激，并启动细胞死亡，这是加剧了许多环境毒素。线粒体ROS还参与信号转导机制，根据确切的生理或环境背景，可能具有有害和有益的结果。然而，线粒体ROS传感机制和特定的应激反应途径，决定这些差异的结果是研究不足，远未理解。理解线粒体病理学以及环境毒素如何促进或加剧它的一个主要限制是涉及线粒体功能和应激反应的复杂组织特异性。也缺乏动物模型，以组织特异性方式或在发育的特定时间产生和监测急性和慢性线粒体应激和毒理学。该提案的R21部分的主要目标是通过线粒体超氧化物歧化酶基因（SOD2）的受控和可逆敲低开发线粒体应激的新型小鼠模型，这将增加线粒体ROS的水平，从而模拟环境毒素暴露并允许系统地识别线粒体至细胞核信号传导途径的特征。使用这些特征，我们将确定环境烟草烟雾（ETS）暴露在小鼠中是否会引起线粒体ROS反应，作为其毒性机制的一部分。在该提案的R33部分中，尖端的线粒体抗氧化剂将用于更精确地定义R21阶段中获得的线粒体ROS应激特征，并防止ETS及其两种高毒性成分多环芳族化合物的有害组织效应。 碳氢化合物B[a]P和重金属Cd。最后，这些新的小鼠模型将用于测试以下概念，即发育过程中产生的线粒体ROS导致适应性信号传导反应，该反应决定了成年人对随后毒素暴露的抵抗性质或程度。这项研究的结果将极大地扩展线粒体和ROS信号在环境应激诱导的毒性和复杂的组织特异性病理学中的作用的知识，并将为未来旨在监测，诊断和可能抵消这些的研究提供信息。

 DESCRIPTION (provided by applicant): Mitochondria are essential, multi-functional organelles that control metabolism, but are also targets of environmental stress and involved in human disease pathology. Mitochondria produce reactive oxygen species (ROS) that damage macromolecules, promote oxidative stress, and initiate cell death that is exacerbated by many environmental toxins. Mitochondrial ROS also participate in signal transduction mechanisms that can have both detrimental and beneficial outcomes, depending on the exact physiological or environmental context. However, the mechanisms of mitochondrial ROS sensing and the specific stress-response pathways that determine these differential outcomes are understudied and far from understood. A major limitation in understanding mitochondrial pathology, and how environmental toxins promote or exacerbate it, is the complex tissue-specificity involved in mitochondrial function and stress responses. There is also a dearth of animal models in which to generate and monitor acute and chronic mitochondrial stress and toxicology in a tissue-specific manner or at specific times in development. The major goal of the R21 portion of this proposal is to develop novel mouse models of mitochondrial stress via controlled AND reversible knock-down of the mitochondrial superoxide dismutase gene (SOD2), which will increase the levels of mitochondrial ROS, and hence model environmental toxin exposures and allow mitochondria-to-nucleus signaling pathway signatures to be identified systematically. Using these signatures, we will then determine if environmental tobacco smoke (ETS) exposure in mice evokes a mitochondrial ROS response as part of its toxic mechanism. In the R33 portion of this proposal, cutting-edge mitochondrial antioxidants will be used to more precisely define the mitochondrial ROS stress signatures obtained in the R21 Phase and to prevent the deleterious tissue effects of ETS and two of its highly toxic constituents, the polycyclic aromatic hydrocarbon B[a]P and the heavy metal Cd. Finally, these new mouse models will be used to test the concept that mitochondrial ROS produced during development result in adaptive signaling responses that determine the nature or degree of resistance to subsequent toxin exposures in adults. The results of this study will greatly expand knowledge of the role of mitochondria and ROS signaling in environmental stress-induced toxicity and the complex tissue-specific pathology involved, and will inform future studies aimed at monitoring, diagnosing, and perhaps counteracting these.