Manganese and basal ganglia dysfunction: role of NO

锰和基底神经节功能障碍：NO 的作用

基本信息

批准号：
7848508
负责人：
RONALD TJALKENS
金额：
$ 1.71万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-16 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848508
关键词：
Adult Animals Apoptosis Astrocytes Basal Ganglia Basal Ganglia Diseases Brain region Cell Communication Cells Cellular biology Chronic Clinical Core Facility Data Degenerative Disorder Development Disease Environment Event Experimental Models Fostering Functional disorder Funding Gene Expression Gene Expression Regulation General Population Genes Genetic Goals Human Huntington Disease Imagery Inflammatory Injury Intoxication Knowledge Laboratories Manganese Mediating Metals Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate Movement Disorders NF-kappa B NOS2A gene Neonatal Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Neurosciences Nitric Oxide Normal Cell Parkinson Disease Pathogenesis Pathway interactions Play Predisposition Production Regulation Research Research Personnel Resources Role Signal Pathway Signal Transduction Signaling Molecule Source Stress Study Section Testing Therapeutic Transgenic Mice Work age related base dietary trace element expectation human NOS2A protein in vivo innovation mortality mouse model nervous system disorder neurotoxic neurotoxicity prevent programs response

项目摘要

DESCRIPTION (provided by applicant): Chronic intoxication with manganese (Mn) is the cause of a degenerative movement disorder, termed manganism, with clinical features that resemble Parkinson's disease. Recent findings suggest that injury to this region of the brain involves perturbation of the normally supportive function of glial cells to an activated state that results in increased expression of inflammatory genes such as inducible nitric oxide synthase (NOS2), that can subsequently produce neurotoxic levels of nitric oxide (NO). Similar deleterious neuro-glial interactions occur in other degenerative disorders of the basal ganglia, such as Parkinson's and Huntington's diseases, highlighting the need to elucidate the mechanisms underlying these damaging interactions. The long-term goal of this research program is to better understand role of glial cells in the pathogenesis of diseases of the basal ganglia. The objective of this application is to identify mechanisms underlying glial-mediated neuronal injury in an experimental model of manganism. The central hypothesis is that Mn exposure results in glial activation and expression of NOS2 that contributes to age-dependent neuronal injury and debilitation of basal ganglia function through overproduction of NO. This hypothesis will be tested by pursuing two specific aims: 1) Determine the Mn-dependent signals that cause induction of NOS2 in astroglial cells. The working hypothesis for this aim is that Mn increases NF-KappaB-dependent expression of NOS2 by activating specific MAP kinases. 2) Identify the mechanisms underlying age-dependent susceptibility of the basal ganglia to manganese. It is postulated under this aim that Mn-mediated production of NO during development results in glial activation and neuronal injury that decreases the threshold for basal ganglia dysfunction upon subsequent exposures. The experimental approach proposed utilizes genetic interdiction of specific signaling molecules in the NF-KappaB pathway to identify critical upstream activators of NOS2 expression in astroglial cells. The activity of the factors identified will be quantified in relation to activity of NF-KappaB and expression of NOS2 in neonatal and adult wildtype and transgenic mice exposed to Mn. It is expected that this innovative approach will identify important early targets of Mn that promote neuronal injury by increased synthesis of NO. The proposed research is significant, because it is expected to advance understanding of the pathogenic role of glial-derived NO in disorders of the basal ganglia and, thereby, to foster the development of neuroprotective therapeutic strategies that target inflammatory signaling pathways in glial cells.

描述（由申请人提供）：用锰（MN）长期陶醉是一种变性运动障碍的原因，称为锰，具有类似于帕金森氏病的临床特征。最近的发现表明，对大脑区域的损伤涉及神经胶质细胞正常支持的功能对激活状态的扰动，从而导致炎性基因（例如诱导型一氧化氮合酶（NOS2））的表达增加，从而可以随后产生氮氧化氮的神经毒性水平（NO）。类似的有害神经胶质相互作用发生在基底神经节的其他退化性疾病中，例如帕金森氏症和亨廷顿疾病，强调了阐明这些有害相互作用的机制的需求。该研究计划的长期目标是更好地了解神经胶质细胞在基底神经节疾病的发病机理中的作用。该应用的目的是确定在锰制的实验模型中神经胶质介导的神经元损伤的机制。中心假设是，MN暴露会导致NOS2的神经胶质激活和表达，从而导致年龄依赖性的神经元损伤以及基底神经节功能的衰弱，这是通过过量生产NO的。该假设将通过追求两个具体目的来检验：1）确定导致星形胶质细胞中NOS2诱导的MN依赖性信号。该目标的工作假设是MN通过激活特定的MAP激酶来增加NF-kappab依赖性NOS2的表达。 2）确定基底神经节对锰的年龄依赖性敏感性的基础机制。在此目的下，MN介导的NO在发育过程中的产生导致神经胶质激活和神经元损伤降低了基底神经节功能障碍在随后的暴露后降低阈值。提出的实验方法利用了NF-kappab途径中特定信号分子的遗传拦截，以鉴定星形胶质细胞中NOS2表达的关键上游激活剂。确定因素的活性将根据NF-kappab的活性以及在新生儿和成人野生型和暴露于MN的转基因小鼠中的活性以及NOS2的表达进行量化。预计这种创新的方法将确定MN的重要早期靶标，这些靶标通过增加NO的合成来促进神经元损伤。拟议的研究很重要，因为有望提高人们对基底神经节疾病中神经胶质衍生的NO的致病作用的了解，从而促进靶向靶向神经胶质细胞炎症信号通路的神经保护治疗策略的发展。