Toxicant, oxidative injury, dopamine & synuclein in PD

有毒、氧化损伤、多巴胺

基本信息

  • 批准号:
    7515345
  • 负责人:
  • 金额:
    $ 28.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-12-08 至 2011-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of nigrostriatal dopaminergic neurons. The etiology of sporadic Parkinson's disease remains unknown although epidemiologic studies implicate to gene environment interaction. Progress in Parkinson's disease modeling in rodents has been achieved by administration of specific toxicants and through construction of transgenic mice harboring human a-synuclein. The pathogenic linkage between toxicant and a-synuclein appears to lie in their unique capacities to produce oxidative injury. Less well investigated is role of glial-neuronal interactions promoting oxidative damage and death of ventral midbrain dopamine neurons. We hypothesize that neuronal overexpression of \vildtype human a-synuclein triggers ROS that are, in part, defended by local glial anti-oxidant responses. Over time this defense mechanism fails resulting in pathologic a-synuclein misfolding, presynaptic dopamine neuron injury and ultimately cell death. To test each facet of this hypothesis, we engineered a compound transgenic mouse to specifically overexpress human wild type a-synuclein in dopaminergic cells (SYN+/+) on the background of glial depleted glutathione peroxidase 1 (GPX-/-) and an antioxidant promoter-reporter. This compound transgenic animal (SYN+/+::GPX-/-::AREhPLAP) affords the study of and cellular locus of oxidative injury wrought by a-synuclein and the impact of impaired glial anti-oxidant capacity on dopaminergic neuron function and viability. Three Aims have been proposed. Aim 1. The evolution of oxidant injury in human wild type a-synuclein homozygous mice (SYN+/+::AREhPLAP). Aim 2. Synergistic injury in SYN+/+::GPX-/-::AREhPLAP mice: a model of accelerated dopaminergic neuron compromise. Aim 3 In which cell types does restoration ofGpx-1 mitigate environmental toxicant injury in SYN+/+::GPX-/-::AREhPLAP mice. These studies will produce clear and interpretable data concerning the role of glia anti-oxidant defense in oxidative injury elicited by a-synuclein alone and in combination with a known dopaminergic toxicant. The mechanistic information derived may enable new glial-oriented therapeutic initiatives.
描述(由申请人提供):帕金森病(PD)是一种神经退行性疾病,其特征是黑质纹状体多巴胺能神经元丢失。尽管流行病学研究表明帕金森病的发病与基因和环境的相互作用有关,但其病因学仍不清楚。通过给予特定毒物和通过构建携带人α-突触核蛋白的转基因小鼠,在啮齿动物中建立帕金森病模型已经取得了进展。毒物和α-突触核蛋白之间的致病联系似乎在于它们产生氧化损伤的独特能力。较少研究的是神经胶质-神经元相互作用促进腹侧中脑多巴胺神经元氧化损伤和死亡的作用。我们假设,神经元过表达的\vildtype人类α-突触核蛋白触发ROS,部分是由当地的神经胶质细胞抗氧化反应。随着时间的推移,这种防御机制失败,导致病理性α-突触核蛋白错误折叠,突触前多巴胺神经元损伤和最终细胞死亡。为了测试这一假设的各个方面,我们设计了一种复合转基因小鼠,以在胶质细胞耗尽型谷胱甘肽过氧化物酶1(GPX-/-)和抗氧化剂启动子-报告基因的背景下,在多巴胺能细胞(SYN+/+)中特异性过表达人野生型α-突触核蛋白。该复合转基因动物(SYN+/+::GPX-/-::AREhPLAP)提供了对α-突触核蛋白引起的氧化损伤的细胞位点以及受损的神经胶质抗氧化能力对多巴胺能神经元功能和存活力的影响的研究。提出了三个目标。目标1.人类野生型α-突触核蛋白纯合小鼠(SYN+/+::AREhPRAP)中氧化损伤的演变。目标二。SYN+/+::GPX-/-::AREhPLAP小鼠中的协同损伤:加速多巴胺能神经元损害的模型。目的3 Gpx-1基因的修复对SYN+/+::GPX-/-::AREhPLAP小鼠环境毒物损伤的减轻作用在哪种细胞类型中起作用。这些研究将产生关于神经胶质抗氧化防御在由α-突触核蛋白单独和与已知多巴胺能毒物组合引起的氧化损伤中的作用的明确和可解释的数据。所得到的机制信息可能使新的神经胶质导向的治疗举措。

项目成果

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Kathleen Anne Maguire-Zeiss其他文献

Kathleen Anne Maguire-Zeiss的其他文献

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{{ truncateString('Kathleen Anne Maguire-Zeiss', 18)}}的其他基金

Georgetown University Initiative for Maximizing Student Development (IMSD)
乔治城大学最大化学生发展倡议(IMSD)
  • 批准号:
    10359915
  • 财政年份:
    2022
  • 资助金额:
    $ 28.8万
  • 项目类别:
Georgetown University Initiative for Maximizing Student Development (IMSD)
乔治城大学最大化学生发展倡议(IMSD)
  • 批准号:
    10551835
  • 财政年份:
    2022
  • 资助金额:
    $ 28.8万
  • 项目类别:
Neural Injury and Plasticity Training Program
神经损伤与可塑性训练计划
  • 批准号:
    10226116
  • 财政年份:
    2017
  • 资助金额:
    $ 28.8万
  • 项目类别:
Neural Injury and Plasticity Training Program
神经损伤与可塑性训练计划
  • 批准号:
    9769906
  • 财政年份:
    2017
  • 资助金额:
    $ 28.8万
  • 项目类别:
Neural Injury and Plasticity Training Program
神经损伤与可塑性训练计划
  • 批准号:
    9278596
  • 财政年份:
    2017
  • 资助金额:
    $ 28.8万
  • 项目类别:
Training in Neural Injury and Plasticity
神经损伤和可塑性培训
  • 批准号:
    8694910
  • 财政年份:
    2013
  • 资助金额:
    $ 28.8万
  • 项目类别:
Toxicant, oxidative injury, dopamine & synuclein in PD
有毒、氧化损伤、多巴胺
  • 批准号:
    7536098
  • 财政年份:
    2006
  • 资助金额:
    $ 28.8万
  • 项目类别:
Toxicant, oxidative injury, dopamine & synuclein in PD
有毒、氧化损伤、多巴胺
  • 批准号:
    7991325
  • 财政年份:
    2006
  • 资助金额:
    $ 28.8万
  • 项目类别:
Toxicant, oxidative injury, dopamine & synuclein in PD
有毒、氧化损伤、多巴胺
  • 批准号:
    7196862
  • 财政年份:
    2006
  • 资助金额:
    $ 28.8万
  • 项目类别:
Toxicant, oxidative injury, dopamine & synuclein in PD
有毒、氧化损伤、多巴胺
  • 批准号:
    7328616
  • 财政年份:
    2006
  • 资助金额:
    $ 28.8万
  • 项目类别:

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