Mycobacterium tuberculosis-manganese interactions and neurotoxicity

结核分枝杆菌-锰的相互作用和神经毒性

基本信息

批准号：
9018737
负责人：
NIKOLAY M FILIPOV
金额：
$ 22.5万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9018737
关键词：
Address Affect Africa South of the Sahara Astrocytes Autopsy Bacterial Infections Basal Ganglia Basal Ganglia Diseases Brain Cell Line Chronic Comorbidity Data DsRed Environment Epidemiology Exposure to Globus Pallidus Goals HIV Infections High Prevalence Human In Vitro Incidence Individual Infection Infectious Agent Inflammation Inflammation Mediators Inflammatory Inhalation Exposure Institutes Invaded Knowledge Label Lead Lesion Lipopolysaccharides Lung Manganese Metals Methods Microglia Mining Molecular Mus Mycobacterium tuberculosis Nature Neuroglia Neurologic Neurons Neurotoxins Occupational Health Output Parkinson Disease Parkinsonian Disorders Peripheral Predisposition Prevalence Pulmonary Tuberculosis Reporting Research Risk Role South Africa Staging Testing Time Toll-like receptors Toxic effect Tuberculosis Work base cell type cytokine dopaminergic neuron drinking water expectation glial activation high risk in vivo indexing innovation macrophage mortality mouse model neurochemistry neuroinflammation neuropathology neurotoxic neurotoxicity public health relevance toxicant transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Overexposure to manganese (Mn) results in a parkinsonian disorder, manganism, which is clearly associated with basal ganglia lesions that include aberrations of neuroinflammatory nature and is best characterized in Mn miners. Besides Mn overexposure, Mn miners also have the highest prevalence of tuberculosis (TB), suggesting high likelihood of co-exposure to Mn and Mycobacterium tuberculosis (Mtb). However, the nature of the Mn-Mtb interaction within the context of Mn-induced neuropathology has not been studied until now. Our broader objectives are to study and decipher the mechanisms of Mn neurotoxicity within the context of exposure scenarios and co-morbidities, such as TB, that are of high human relevance. Hence, using complementary mouse models and in vitro approaches, combined with innovative and occupationally-relevant delivery method (intratracheal sprayer), and based on exciting preliminary data we will investigate the Mn-Mtb interaction from a Mn neuropathology perspective. We hypothesize that Mn and Mtb will interact both within the brain and in the periphery, such that combined Mn/Mtb exposure will lead to increased neuroinflammation, increased peripheral inflammation, and increased neuronal susceptibility to the effects of Mn. This hypothesis will be tested with the following two specific aims: (1) to determine the nature of the interaction between Mn and Mtb and to evaluate the neurotoxicity caused by co-administration of Mn and Mtb directly into the brain (globus pallidus) or by intratracheal Mn and Mtb exposure and (2) to determine whether direct Mtb infection of neurons modulates the neurotoxicity of Mn and whether such modulation is neuronal cell-type specific. Collectively, the work proposed in aims 1 and 2 will enable us to determine the role of TB comorbidity in the neuropathology associated with Mn overexposure. Such results will have transformative positive impact because they will be the first to report on a highly epidemiologically-relevant toxicant (Mn) and infectious agent (Mtb) interaction. The proposed studies will also have potential broader consequences to other conditions where bacterial infections in the face of metal excess (or deficiency) are of concern.

描述（由申请人提供）：过度接触锰 (Mn) 会导致帕金森病、锰中毒，这显然与基底神经节病变相关，其中包括神经炎症性质的异常，并且在锰矿工中最为明显。结核病 (TB) 患病率最高，表明同时接触锰和结核分枝杆菌的可能性很高(Mtb). 然而，到目前为止，我们还没有研究锰诱导的神经病理学背景下锰-结核分枝杆菌相互作用的性质，我们更广泛的目标是研究和破译暴露场景和环境下锰神经毒性的机制。 -与人类高度相关的疾病，例如结核病，因此，使用互补的小鼠模型和体外方法，结合创新和职业相关的输送方法（气管内喷雾器），并基于令人兴奋的初步结果。根据数据，我们将从 Mn 神经病理学角度研究 Mn-Mtb 相互作用。我们认为 Mn 和 Mtb 会在大脑内和外周相互作用，因此 Mn/Mtb 联合暴露将导致神经炎症增加、外周炎症增加，并且神经对锰影响的敏感性增加这一假设将通过以下两个具体方面进行检验。目的：(1) 确定 Mn 和 Mtb 之间相互作用的性质，并评估将 Mn 和 Mtb 直接同时给予大脑（苍白球）或通过气管内 Mn 和 Mtb 暴露引起的神经毒性；(2)确定神经元的直接 Mtb 感染是否会调节 Mn 的神经毒性，以及这种调节是否具有神经元细胞类型特异性。总的来说，目标 1 和 2 中提出的工作将能够实现。我们将确定结核病合并症在与锰过度暴露相关的神经病理学中的作用，这样的结果将产生变革性的积极影响，因为它们将是第一个报告提出的与流行病学高度相关的毒物（Mn）和传染原（Mtb）的相互作用。研究还将对其他因金属过量（或缺乏）而引起细菌感染的情况产生潜在的更广泛的影响。