Nocardia: A Novel Environmental Agent For Parkinsonism?

诺卡氏菌:​​帕金森病的新型环境因子?

基本信息

  • 批准号:
    6326525
  • 负责人:
  • 金额:
    $ 34.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2001
  • 资助国家:
    美国
  • 起止时间:
    2001-08-01 至 2004-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (Adapted from applicant's abstract): The acid-fast bacterium Nocardia asteroides (NA) is widespread in the environment, and subclinical human infection is common. Experimental infection of mice with this organism results in loss of nigrostriatal dopaminergic neurons, decreased striatal dopamine concentration, and movement abnormalities including head shaking and slowness of movement. These neurochemical and motor alterations are similar to those in Parkinson's disease (PD). The long range goal of our studies is to determine how and why neurons in the substantia nigra pars compacta (SNpc) deteriorate in PD. The objective of this application is to determine the relevance of NA infection as an animal model for PD and a potential causative agent of PD. Our central hypothesis is that CNS NA infection results in the specific loss of dopaminergic neurons and development of motor abnormalities by mechanisms similar to those suggested for PD. This hypothesis has been formulated on the basis of strong preliminary data, suggesting that (a) nocardial toxicity in the SNpc is dopamine neuron-specific, (b) histological findings, including dopamine neuron loss and development of Lewy body-like inclusions, are similar to those in PD, and (c) some of the movement abnormalities in these animals result from striatal dopamine depletion, because they respond to levodopa administration. The rationale for this research is that an understanding of the process by which experimental NA infection causes loss of dopaminergic neurons and motor abnormalities may enhance our ability to prevent this process in PD. Nocardia may be a cause of PD because the organism can survive long-term in the brain as an L-form, suggesting that chronic, subclinical infection could result in neurodegeneration. We are uniquely qualified to perform this research because of our experience with the various in vivo and in vitro aspects of this model. The central hypothesis will be tested and the objective of the application accomplished by pursuing three specific aims: (1) Determine the relationship between neurological and motor abnormalities in mice experimentally infected with NA, and the relevance of this model to PD, (2) Characterize the specificity and mechanism of NA toxicity, and (3) Determine whether evidence for NA infection can be detected in brain specimens from NA-infected mice and from human subjects with PD and Parkinsonian-like syndromes. This work is innovative because it explores the novel hypothesis that an infectious agent may offer a new model for PD and may even contribute to the disease. It is our expectation that these studies will reveal the extent to which this animal model resembles PD, as well as whether persistent NA infection occurs in the PD brain. These outcomes will be significant because they should add to our understanding of the neurodegenerative process in PD, and could lead to improved means of diagnosis and treatment for individuals with this disorder.
描述(改编自申请人的摘要):抗酸细菌 小行星诺卡氏菌 (NA) 在环境中广泛存在,且亚临床 人类感染很常见。用这种生物体实验性感染小鼠 导致黑质纹状体多巴胺能神经元丧失,纹状体减少 多巴胺浓度和运动异常,包括摇头和 运动缓慢。这些神经化学和运动改变类似于 那些患有帕金森病(PD)的人。我们研究的长期目标是 确定黑质致密部 (SNpc) 神经元的方式和原因 PD 恶化。该应用程序的目的是确定 NA 感染作为 PD 动物模型和潜在病因的相关性 PD的代理人。我们的中心假设是 CNS NA 感染导致 多巴胺能神经元的特异性丧失和运动异常的发展 机制与针对 PD 所建议的机制类似。这一假设已被 根据强有力的初步数据制定,表明 (a) SNpc 诺卡氏菌毒性是多巴胺神经元特异性的,(b) 组织学 研究结果,包括多巴胺神经元损失和路易体样发育 内含物,与 PD 中的类似,并且 (c) 一些运动 这些动物的异常是纹状体多巴胺耗竭造成的,因为 他们对左旋多巴给药有反应。这项研究的理由是 了解实验性 NA 感染引起的过程 多巴胺能神经元的丧失和运动异常可能会增强我们的能力 在 PD 中阻止此过程。诺卡氏菌可能是 PD 的一个原因,因为该生物体 可以以 L 型形式在大脑中长期存活,这表明慢性、 亚临床感染可能导致神经变性。我们是独一无二的 由于我们在各种方面的经验,有资格进行这项研究 该模型的体内和体外方面。中心假设将是 经过测试并通过追求三个目标来实现应用程序的目标 具体目标:(1)确定神经学和运动学之间的关系 实验性感染 NA 的小鼠的异常情况以及相关性 将此模型转化为PD,(2)表征NA的特异性和机制 毒性,以及 (3) 确定是否可以检测到 NA 感染的证据 NA 感染小鼠和患有 PD 的人类受试者的脑标本中 帕金森样综合症。这项工作具有创新性,因为它探索了 新的假设认为,传染源可能为帕金森病提供一种新模型,并且可能 甚至促成疾病。我们期望这些研究能够 揭示该动物模型与 PD 的相似程度,以及是否 持续性 NA 感染发生在 PD 大脑中。这些结果将是 意义重大,因为它们应该增加我们对 PD 的神经退行性过程,可能会导致诊断手段的改进 以及对患有这种疾病的个体的治疗。

项目成果

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PETER A LEWITT其他文献

PETER A LEWITT的其他文献

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{{ truncateString('PETER A LEWITT', 18)}}的其他基金

Southeastern Michigan Parkinson's Disease Program
密歇根州东南部帕金森病项目
  • 批准号:
    7013965
  • 财政年份:
    2002
  • 资助金额:
    $ 34.37万
  • 项目类别:
Southeastern Michigan Parkinson's Disease Program
密歇根州东南部帕金森病项目
  • 批准号:
    6666859
  • 财政年份:
    2002
  • 资助金额:
    $ 34.37万
  • 项目类别:
Southeastern Michigan Parkinson's Disease Program
密歇根州东南部帕金森病项目
  • 批准号:
    6545866
  • 财政年份:
    2002
  • 资助金额:
    $ 34.37万
  • 项目类别:
Nocardia: A Novel Environmental Agent For Parkinsonism?
诺卡氏菌:​​帕金森病的新型环境因子?
  • 批准号:
    6525204
  • 财政年份:
    2001
  • 资助金额:
    $ 34.37万
  • 项目类别:
Nocardia: A Novel Environmental Agent For Parkinsonism?
诺卡氏菌:​​帕金森病的新型环境因子?
  • 批准号:
    6649714
  • 财政年份:
    2001
  • 资助金额:
    $ 34.37万
  • 项目类别:
PARKINSON DISEASE PATHOPHYSIOLOGY--CSF MARKERS
帕金森病病理生理学--脑脊液标志物
  • 批准号:
    3414333
  • 财政年份:
    1990
  • 资助金额:
    $ 34.37万
  • 项目类别:
PARKINSON DISEASE PATHOPHYSIOLOGY--CSF MARKERS
帕金森病病理生理学--脑脊液标志物
  • 批准号:
    3414334
  • 财政年份:
    1990
  • 资助金额:
    $ 34.37万
  • 项目类别:
PARKINSON DISEASE PATHOPHYSIOLOGY--CSF MARKERS
帕金森病病理生理学--脑脊液标志物
  • 批准号:
    3414332
  • 财政年份:
    1990
  • 资助金额:
    $ 34.37万
  • 项目类别:

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