Mitochondrial mechanisms of redox cycling agents

氧化还原循环剂的线粒体机制

基本信息

批准号：
7694259
负责人：
MANISHA N PATEL
金额：
$ 24.93万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7694259
关键词：
1-Methyl-4-phenylpyridinium Aconitate Hydratase Address Aerobic Antioxidants Attenuated Blood - brain barrier anatomy Brain Complex Data Dermal Development Diquat Dopaminergic Cell Electron Transport Electron Transport Complex III Electrons Environment Enzymes Epidemiologic Studies Epidemiology Etiology Exhibits Exposure to Generations Genetic Goals Grant Herbicides Hydrogen Peroxide In Vitro Individual Ingestion Intoxication Investigation Iron Link Literature Mediating Metalloporphyrins Mitochondria Molecular Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neuroprotective Agents Neurotoxins Occupational Oxidants Oxidation-Reduction Oxidative Stress Oxidopamine Paraquat Parkinson Disease Parkinsonian Disorders Play Poisoning Production Reaction Reactive Oxygen Species Reporting Risk Role Rotenone Source Sulfur Superoxides Therapeutic Toxic effect Toxicant exposure aminochrome 1 base dopachrome dopamine quinone dopaminergic neuron environmental agent in vivo injured neurotoxic neurotoxicity novel public health relevance toxicant treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to determine the mechanisms by which environmental agents produce neurodegeneration. Environmental neurotoxicants are strongly implicated in the etiology of neurodegenerative diseases such as Parkinson's disease (PD). Redox cycling agents such as the herbicide paraquat (PQ2+) are found in the environment and several compounds in this class have come under investigation as neurotoxic agents based on the ability to produce reactive oxygen species (ROS) in an aerobic environment and epidemiological reports linking their exposure with increased risk of PD. However, the cellular and molecular mechanisms by which environmental redox cycling agents produce ROS and resultant neurotoxicity remain incompletely understood. It is hypothesized that the mitochondria play a key role in ROS production by redox cycling agents and consequent neurotoxicity. The hypothesis predicts that redox cycling agents such as PQ2+ increase mitochondrial ROS production by a mechanism involving its partial reduction by electrons of the electron transport chain to form the PQ+. radical via complex III as the redox enzyme. The hypothesis further predicts that mitochondria are a target of redox cycling agents and scavenging mitochondrial oxidants will ameliorate neurotoxicity. To address this, the following specific aims are proposed. Specific Aim 1: Determine the mitochondrial mechanism of ROS generation and neurotoxicity by redox cycling agents. Specific Aim 2: Determine if mitochondria are a source and a target of oxidative stress produced by redox cycling agents in dopaminergic cells in vivo. Specific Aim 3: Determine if mitochondrially targeted therapies ameliorate mitochondrial oxidative stress and neurotoxicity produced by in vivo administration of redox cycling agents. These studies can elucidate the mechanism by which exposure to environmental redox cycling agents can injure dopaminergic neurons and provide a rational therapy to treat neurotoxicant-induced Parkinson's disease. PUBLIC HEALTH RELEVANCE A steadily growing body of literature suggests that environmental agents alone, or in combination with genetic factors or other toxicants may predispose individuals to neurodegenerative diseases such as Parkinson's disease (PD). Paraquat and diquat are widely used prototypical redox cycling environmental agents with the potential of causing parkinsonism. The extensive use of these agents as a landscape and aquatic herbicides underscores the importance of their environmental and occupational risk. Therefore, elucidating the molecular mechanisms of such agents and development of rational therapeutic strategies that penetrate the blood brain barrier is critical.

描述（由申请人提供）：该提案的长期目标是确定环境药物产生神经变性的机制。环境神经毒性与神经退行性疾病（如帕金森氏病（PD））的病因强有关。在环境中发现了氧化还原循环剂，例如除草剂paraquat（PQ2+），并且该类别的几种化合物基于神经毒性剂的研究，基于有氧环境中产生反应性氧（ROS）的能力，并在有氧环境中产生反应性氧（ROS），并将其与PD的风险增加相关的流行病学报告。然而，环境氧化还原循环剂产生ROS的细胞和分子机制仍未完全了解。假设线粒体在氧化还原循环剂和随之而来的神经毒性中起关键作用。该假设预测，诸如PQ2+等氧化还原循环剂通过涉及电子传输链电子部分减少的机制增加了线粒体ROS的产生，形成了PQ+。通过复合物III作为氧化还原酶。该假设进一步预测，线粒体是氧化还原循环剂的靶标，并且清除线粒体氧化剂将改善神经毒性。为了解决这个问题，提出了以下特定目标。具体目标1：确定氧化还原循环剂的ROS产生和神经毒性的线粒体机制。具体目标2：确定线粒体是否是由体内多巴胺能细胞中氧化还原循环剂产生的氧化应激的来源和靶标。具体目标3：确定线粒体靶向疗法是否可以改善通过体内给药氧化还原循环剂产生的线粒体氧化应激和神经毒性。这些研究可以阐明暴露于环境氧化还原循环剂的机制，可损害多巴胺能神经元，并提供一种治疗神经毒性诱发的帕金森氏病的合理疗法。公共卫生相关性稳步增长的文献表明，单独的环境药物或与遗传因素或其他有毒物质结合使用，可能会使个体患有神经退行性疾病，例如帕金森氏病（PD）。 Paraquat和Diquat是广泛使用的原型氧化还原循环环境药物，具有引起帕金森氏症的潜力。这些代理作为景观和水生除草剂的广泛使用强调了其环境和职业风险的重要性。因此，阐明这种药物的分子机制以及穿透血脑屏障的理性治疗策略的发展至关重要。