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（由申请方提供）：锰（Mn）过量导致帕金森病，锰中毒，明显与基底神经节病变相关，包括神经炎症性质的畸变，在锰矿工中表现最佳。除了锰过量，锰矿工也有最高的结核病（TB）的患病率，这表明高的可能性，共同暴露于锰和结核分枝杆菌（Mtb）。然而，锰诱导的神经病理学背景下的锰结核相互作用的性质尚未研究，直到现在。我们更广泛的目标是研究和破译锰神经毒性的机制的背景下，暴露的情况和合并症，如结核病，这是人类的高度相关性。因此，使用互补的小鼠模型和体外方法，结合创新的和职业相关的递送方法（气管内喷雾器），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将在脑内和外周中相互作用，使得Mn/Mtb组合暴露将导致神经炎症增加、外周炎症增加和神经元对Mn作用的易感性增加。这一假设将通过以下两个具体的 目的：（1）确定Mn和Mtb之间相互作用的性质，并评价由Mn和Mtb直接共同给药至脑（苍白球）或通过脑内Mn和Mtb暴露引起的神经毒性，和（2）确定神经元的直接Mtb感染是否调节Mn的神经毒性，以及这种调节是否是神经元细胞类型特异性的。总的来说，目标1和2中提出的工作将使我们能够确定结核合并症在与锰过量相关的神经病理学中的作用。这些结果将产生变革性的积极影响，因为它们将是第一个报告高度流行病学相关的毒物（Mn）和感染因子（Mtb）相互作用的结果。拟议的研究还将对其他条件产生潜在的更广泛的影响，在这些条件下，金属过量（或缺乏）时的细菌感染是值得关注的。