Combined dopaminergic neurotoxicity of manganese and LPS

锰和脂多糖的联合多巴胺能神经毒性

• 批准号: 6813095
• 负责人: BIN LIU
• 金额: $ 14.55万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6813095
• 关键词: NAD(P)H dehydrogenase; Parkinson' s disease; cytokine; cytotoxicity; disease /disorder etiology; dopamine; endotoxins; environmental exposure; environmental toxicology; enzyme activity; free radicals; glia; immunocytochemistry; laboratory rat; lipopolysaccharides; manganese; molecular pathology; neural degeneration; neurons; neuropathology; neurotoxicology; oxidative stress; pathologic process; substantia nigra; tissue /cell culture; toxicant interaction

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a movement disorder characterized by a progressive and selective loss of dopamine (DA) neurons in the substantia nigra. At the present, PD affects nearly one million people in the US alone and the incidence is expected to increase with an aging population. The vast majority of PD is idiopathic, occurs late in life, and does not appear to be directly related to gene mutations identified in several familial clusters of early-onset PD. Accumulating evidence indicates that environmental agents including heavy metals and infectious agents represent risk factors for idiopathic PD. The DA neurotoxicity of the heavy metal manganese has been documented and activation of brain immune cells (microglia and astroglia) by bacterial endotoxin lipopolysaccharide (LPS) is known to releases neurotoxic factors to induce neurodegeneration. However, the etiology of PD may be multi-factorial: the development of PD may be a final outcome of chronic exposure to low concentrations of multiple environmental agents. Therefore, this proposal plans to study the combined DA neurotoxicity of low concentrations of the heavy metal manganese and LPS in a chronic primary neuron-gila culture-based model of PD. The mechanism of the combined neurotoxicity will be analyzed at both the cellular and molecular levels. At the cellular level, the relative contribution to the combined neurotoxicity of the primary brain immune cells, microglia, and astroglia will be determined. At the molecular levels, the contribution to neurodegeneration of neurotoxic factors (free radicals and cytokines) by activated gila and the mechanism of neurodegenerative process will be examined. The results of these studies will enable us to gain understanding of the impact of heavy metals and microbial toxins on the DA system. These studies will also be an important component of our long-term goal of understanding the interaction between environmental factors and the nervous system in relation to the etiology of PD and finding effective strategies for the prevention and/or treatment of the disease.

描述（由申请人提供）：帕金森氏病（PD）是一种运动障碍，其特征是尼格拉底虫中多巴胺（DA）神经元的进行性丧失。目前，仅在美国，PD就会影响近100万人，预计随着人口老龄化的发病率将增加。绝大多数PD都是特发性的，发生在生命后期，并且似乎与早期发作PD的几个家族簇中鉴定出的基因突变直接相关。积累的证据表明，包括重金属和感染剂在内的环境药物代表特发性PD的危险因素。已知重金属锰的DA神经毒性已被记录在细菌内毒素脂多糖（LPS）中激活脑免疫细胞（小胶质细胞和星形胶质细胞），可释放神经毒性因子以诱导神经变性。但是，PD的病因可能是多因素的：PD的发展可能是长期暴露于低浓度多种环境药物的最终结果。因此，该提案计划在基于PD的慢性原发性神经元培养模型中研究低浓度的重金属锰和LP的DA神经毒性。联合神经毒性的机制将在细胞和分子水平上分析。在细胞水平上，将确定原代脑免疫细胞，小胶质细胞和星形胶质细胞的联合神经毒性的相对贡献。在分子水平上，将检查对神经毒性因子（自由基和细胞因子）激活的吉拉（GILA）和神经退行性过程的机制的贡献。这些研究的结果将使我们能够了解重金属和微生物毒素对DA系统的影响。这些研究也将是我们长期目标的重要组成部分，即了解环境因素与神经系统与PD病因的相互作用之间的相互作用，并为预防和/或治疗该疾病的病因和找到有效的策略。