INDUCIBLE MOUSE MODELS OF MITOCHONDRIAL ROS SIGNALING AND ENVIRONMENTAL STRESS

线粒体 ROS 信号传导和环境压力的诱导型小鼠模型

• 批准号: 9056630
• 负责人: GERALD SHADEL
• 金额: $ 20.37万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056630
• 关键词: Acute; Address; Adult; Animal Model; Antioxidants; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Cadmium; Cell Death; Cell Nucleus; Cell physiology; Cells; Cellular Structures; Chronic; Complex; DNA Damage; Development; Diagnosis; Disease; Doxycycline; Environmental Pollutants; Environmental Tobacco Smoke; Functional disorder; Future; Gene Expression; Goals; Health; Heavy Metals; Insulin; Knowledge; Lead; Liver; Mediating; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Monitor; Mus; Muscle; Nature; Nuclear; Organelles; Outcome; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Phase; Physiological; Physiological Processes; Production; Property; Reactive Oxygen Species; Research Personnel; Resistance; Role; SOD2 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Sirolimus; Specificity; Stress; Structure of parenchyma of lung; Superoxides; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Toxin; Transgenic Mice; biological adaptation to stress; environmental tobacco smoke exposure; human disease; knock-down; macromolecule; mouse model; novel; prevent; response; small hairpin RNA

 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.

 描述(申请人提供)：线粒体是基本的，多功能的细胞器，控制新陈代谢，但也是环境压力的目标，并参与人类疾病的病理。线粒体产生活性氧物种(ROS)，破坏大分子，促进氧化应激，并引发细胞死亡，而许多环境毒素会加剧这种死亡。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，信号转导机制可能既有不利的结果，也有有益的结果。然而，线粒体ROS感知的机制和决定这些差异结果的特定应激反应途径还没有得到充分的研究，而且还远未被了解。在理解线粒体病理学以及环境毒素如何促进或加剧线粒体病理学方面的一个主要限制是涉及线粒体功能和应激反应的复杂的组织特异性。也缺乏动物模型来产生和监测急性和慢性线粒体应激和毒理学，以组织特异性的方式或在发育的特定时间。本建议R21部分的主要目标是通过可控和可逆的敲除线粒体超氧化物歧化酶基因(SOD2)来建立新的线粒体应激小鼠模型，这将增加线粒体ROS水平，从而模拟环境毒素暴露，并使系统地识别线粒体到核的信号通路信号。利用这些信号，我们将确定环境烟草烟雾(ETS)暴露在小鼠身上是否会引起线粒体ROS反应，作为其毒性机制的一部分。在这项提案的R33部分，将使用尖端线粒体抗氧化剂来更准确地定义在R21阶段获得的线粒体ROS应激信号，并防止ETS及其两种剧毒成分多环芳烃对组织的有害影响 碳氢化合物B[a]P和重金属Cd。最后，这些新的小鼠模型将被用来测试线粒体在发育过程中产生的ROS导致适应性信号反应的概念，该反应决定了成年人对随后的毒素暴露的抵抗力的性质或程度。这项研究的结果将极大地扩展关于线粒体和ROS信号在环境应激诱导的毒性中的作用以及所涉及的复杂的组织特异性病理的知识，并将为未来旨在监测、诊断甚至抵消这些的研究提供参考。