Nocardia: A Novel Environmental Agent For Parkinsonism?

描述(改编自申请人的摘要)：抗酸细菌 星状诺卡氏菌(NA)广泛存在于环境中，且为亚临床 人类感染是很常见的。该菌对小白鼠的实验性感染 结果黑质纹状体多巴胺能神经元丢失，纹状体减少 多巴胺浓度和运动异常，包括摇头和 行动缓慢。这些神经化学和运动改变类似于 帕金森氏症(PD)患者。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 在警局恶化。此应用程序的目标是确定 NA感染作为帕金森病动物模型和潜在致病因素的相关性 警局的特工。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丢失和运动异常的发生 其机制与帕金森病的治疗机制相似。这一假设一直是 根据强劲的初步数据制定，表明(A) SNPC的心脏毒性是多巴胺神经元特异性的，(B)组织学 研究结果，包括多巴胺神经元丢失和路易体样体的发展 包裹体，类似于Pd中的那些，以及(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 他们对左旋多巴管理有反应。这项研究的基本原理是 对实验性甲型流感感染引起的过程的理解 多巴胺能神经元的丧失和运动异常可能会增强我们 在帕金森病患者中防止此过程。诺卡氏菌可能是帕金森病的原因之一，因为 能以L的形式在大脑中长期存活，提示慢性， 亚临床感染可能导致神经变性。我们独一无二 我们有资格进行这项研究，因为我们在各种 这一模型的体内和体外方面的研究。中心假设将是 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)确定神经和运动之间的关系 实验感染NA的小鼠的异常及其与 该模型对PD，(2)表征了NA的特异性和作用机制 毒性，以及(3)确定是否可以检测到NA感染的证据 在NA感染的小鼠和患有帕金森病和人类的受试者的脑标本中 帕金森病样综合征。这项工作具有创新性，因为它探索了 一种新的假设，即感染性病原体可能为帕金森病提供一种新的模型，并可能 甚至会导致这种疾病。我们期望这些研究将 揭示这种动物模型在多大程度上类似于帕金森病，以及 持续的NA感染发生在帕金森病的大脑中。这些结果将是 有重要意义，因为它们应该增加我们对 帕金森病的神经退行性变过程，并可能导致诊断手段的改进 以及对患有这种疾病的个人的治疗。

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.