Mycobacterium tuberculosis-manganese interactions and neurotoxicity

结核分枝杆菌-锰的相互作用和神经毒性

• 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
• 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

 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（由适用提供）：过度暴露于锰（MN）会导致帕金森氏症，锰，显然与基本的神经节病变有关，其中包括神经炎性性质的畸变，并且在MN矿工中最好地表征。除MN过度暴露外，MN矿工还具有结核病（TB）的最高患病率，这表明共同暴露于MN和结核分枝杆菌（MTB）的可能性很高。但是，直到现在，尚未研究MN-MTB相互作用的性质。我们更广泛的目标是在暴露场景和合并症（例如结核病）中研究和破译MN神经毒性的机制，这些机制具有很高的人类相关性。因此，使用互补的小鼠模型和体外方法，结合了创新和相关的输送方法（气管内喷雾剂），并基于令人兴奋的初步数据，我们将从MN神经病理学的角度研究MN-MTB相互作用。我们假设MN和MTB在大脑和周围之间都会相互作用，因此MN/MTB的联合暴露将导致神经炎症增加，周围感染增加，并增加神经元对MN影响的敏感性。该假设将通过以下两个进行检验。具体的 目的：（1）确定MN和MTB之间相互作用的性质，并评估由Mn和MTB直接在大脑中进行的神经毒性，而在气管内MN和MTB暴露和（2）是否直接MTB感染MTB的MTB感染MN和MTB感染MN和MTB是MTB的神经毒性调节性，MN细胞类型的特异性。总体而言，目标1和2中提出的工作将使我们能够确定结核病合并症在与MN过度暴露相关的神经病理学中的作用。这样的结果将具有变革性的积极影响，因为它们将是第一个报告高度流行病学上的毒物（MN）和传染剂（MTB）相互作用的人。拟议的研究还将对其他疾病产生潜在的广播后果，而这些疾病面对金属的细菌感染超过（或缺乏）引起了人们的关注。