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
• 负责人: PETER A LEWITT
• 金额: $ 34.37万
• 依托单位: WILLIAM BEAUMONT HOSPITAL RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649714
• 关键词: Actinomycetales; Parkinson's disease; disease /disorder etiology; disease /disorder model; dopamine; histopathology; laboratory mouse; model design /development; neural degeneration; neurotoxicology; nocardiosis; substantia nigra

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（改编自申请人摘要）：耐酸细菌 星状诺卡氏菌（NA）广泛存在于环境中， 人类感染是常见的。用这种微生物感染小鼠的实验 导致黑质纹状体多巴胺能神经元的损失， 多巴胺浓度和运动异常，包括摇头和 动作缓慢。这些神经化学和运动改变类似于 帕金森病（Parkinson's Disease，PD）我们研究的长期目标是 确定黑质神经元（SNpc）如何以及为什么 在PD中恶化。本申请的目的是确定 NA感染作为PD动物模型的相关性和潜在病因 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损失和运动异常的发展， 类似于PD的机制。这一假设一直被 根据强有力的初步数据制定，表明（a） SNpc中的诺卡氏菌毒性是多巴胺神经元特异性的，（B）组织学 结果，包括多巴胺神经元损失和路易体样的发展， 夹杂物，是类似于那些在PD，和（c）一些运动 这些动物的异常是由于纹状体多巴胺耗竭，因为 它们对左旋多巴给药有反应。这项研究的基本原理是 对实验性NA感染导致 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中阻止这个过程。诺卡氏菌可能是PD的原因之一，因为该微生物 可以在大脑中以L型长期存活，这表明慢性， 亚临床感染可导致神经变性。我们是唯一 有资格进行这项研究，因为我们的经验与各种 in vivo体内and in vitro外aspects方面of this model模型.核心假设是 测试和应用程序的目标实现追求三个 具体目标：（1）确定神经和运动之间的关系 实验性感染NA的小鼠的异常以及与NA的相关性 （2）探讨NA的特异性和作用机制 毒性，和（3）确定是否可以检测到NA感染的证据 在来自NA感染小鼠和患有PD的人类受试者的脑标本中， 类帕金森综合征这项工作是创新的，因为它探讨了 一种新的假设，即感染因子可能为PD提供一种新的模型， 甚至会导致疾病我们希望这些研究将 揭示这种动物模型与PD相似的程度，以及是否 持续性NA感染发生在PD脑中。这些结果将是 重要的是，它们应该增加我们对 神经退行性过程中的PD，并可能导致改善诊断手段 以及对患有这种疾病的人的治疗。

项目成果

Nocardia asteroides-Induced movement abnormalities in mice: Relevance for Parkinson's disease?

• DOI: 10.1002/mds.26711
• 发表时间: 2016-08
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Loeffler DA;LeWitt PA;Camp DM
• 通讯作者: Camp DM

Comparison of PCR and culture for detection of Nocardia asteroides in brain specimens from experimentally infected BALB/c mice.

PCR 和培养物检测实验感染 BALB/c 小鼠脑标本中小行星诺卡氏菌的比较。

• DOI: 10.1016/j.micres.2004.05.003
• 发表时间: 2004
• 期刊: Microbiological research.
• 作者: Loeffler,DavidA;Camp,DianneM;Nichols,LihuaQu;Maksaereekul,Saipiroon;Beaman,BlaineL;LeWitt,PeterA
• 通讯作者: LeWitt,PeterA