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Role of Copper in LPS-mediated microglial activation

铜在 LPS 介导的小胶质细胞激活中的作用

基本信息

批准号：
8708857
负责人：
Alba Rossi-George
金额：
$ 24.32万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-16 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708857
关键词：
Acute Address Adoption Affect Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Apoptosis Award Basal Ganglia Biological Models Blood Vessels Brain Brain Pathology Cell Culture Techniques Cell physiology Cells Chronic Communication Copper Development Disease Environment Environmental Risk Factor Enzymes Event Excision Exhibits Exposure to Failure Functional disorder Homeostasis Human body Immune Induction of Apoptosis Inflammatory Laboratories Lead Lipopolysaccharides Mediating Mediator of activation protein Mentors Metabolic Microglia Modeling Mus NF-kappa B Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurologic Neurological outcome Neuronal Injury Neurons Nitric Oxide Oxidation-Reduction Parkinson Disease Pathway interactions Phagocytosis Phase Phenotype Play Primary Lateral Sclerosis Prostaglandins Protein Biosynthesis Proteins Proto-Oncogene Protein p21(ras)Regulation Research Project Grants Rest Role Series Signal Transduction Signaling Molecule Structure Sulfhydryl Compounds Surveys Toxin Trace Elements Transition Elements Weather abstracting cell growth regulation chemokine cytokine cytotoxic injured macrophage mutant neuropathology novel therapeutics pathogen respiration regulation response toxicant

项目摘要

Abstract: Microglia are critical to maintaining the internal environment of the central nervous system (CNS). These specialized resident cells function to nourish and support neurons and to act as a first line of defense in response to neuronal injury. In response to a neuropathological state, quiescent microglia undergo a series of changes that result in the release of proinflammatory and cytotoxic mediators for the removal of the pathogen. Upon clearance of injured cells by phagocytosis and/or the removal of toxin and toxicants, microglia return to a resting state or undergo programmed cell death. Microglia, therefore, exhibit different phenotypes depending on their surrounding environment. Expression of the appropriate phenotype is critical to the successful removal of the pathogen and to limiting damage to surrounding neurons. Chronic microglial activation has been observed in a variety of neurodegenerative diseases but, to date, it is not clear whether microglial activation is due to a persistent neuronal degeneration that warrants their activated state, or to microglial dysfunction, including a failure to either upregulate or downregulate the release of cytotoxic mediators including nitric oxide (NO). NOis both a potent cytotoxic mediator and a key regulator of cellular signaling within microglia. Our hypothesis is that the phenotypic response of microglia to toxin exposure is dependent on the metabolic fate of NO. Redox active transition metals have been proposed as important factors in neurodegenerative diseases including Alzheimer's, Parkinson's and amiotropic lateral sclerosis. Levels of the transition metal copper are strictly regulated and deviations will alter NO signaling by changing the redox environment of the cell, particularly in reference to thiols. I propose to investigate the mechanisms by which copper alters copper- stimulated NO signaling and, thus, the phenotypic response of microglia. During the mentored phase of the award in the laboratory of Dr. Andrew Gow, I will investigate the effects of copper on phenotypic differentiation in immortalized BV-2 and in primary microglia cell cultures. In particular, I will examine how copper alters key- signaling molecules and the S-nitrosylation profile in response to an acute toxin challenge and how the presence of copper might interfere with the adoption of an adaptive inflammatory phenotype. The independent phase of the award will build upon the findings obtained during the mentored phase. During this phase I will investigate the effects of chronic copper overload on microglia phenotypic changes in specific anatomical brain structures in response to systemic LPS challenge in the tx j mouse. The effects of chronic copper overload will also be investigated with respect to whether the effects on microglia phenotype are permanent or can be reversed after excess copper has been removed.

抽象的：小胶质细胞对于维持中枢神经系统（CNS）的内部环境至关重要。这些专门的驻留细胞的功能是滋养和支持神经元，并充当第一道防线对神经元损伤的反应。为了响应神经病理状态，静止的小胶质细胞经历一系列导致促炎和细胞毒性介质释放以清除病原体的变化。通过吞噬作用清除受损细胞和/或去除毒素和毒物后，小胶质细胞恢复到正常状态静息状态或经历程序性细胞死亡。因此，小胶质细胞表现出不同的表型，具体取决于关于他们周围的环境。适当表型的表达对于成功去除至关重要病原体并限制对周围神经元的损害。慢性小胶质细胞激活在多种神经退行性疾病中观察到，但迄今为止，尚不清楚小胶质细胞激活是否与由于持续的神经元变性需要其激活状态，或小胶质细胞功能障碍，包括未能上调或下调细胞毒性介质（包括一氧化氮）的释放（不）。 NO 既是一种有效的细胞毒性介质，也是小胶质细胞内细胞信号传导的关键调节剂。我们的假设是小胶质细胞对毒素暴露的表型反应取决于不。氧化还原活性过渡金属已被认为是神经退行性疾病的重要因素包括阿尔茨海默氏症、帕金森氏症和肌萎缩侧索硬化症。过渡金属铜的含量为严格调节和偏差将通过改变细胞的氧化还原环境来改变NO信号传导，特别是关于硫醇。我建议研究铜改变铜的机制刺激 NO 信号传导，从而刺激小胶质细胞的表型反应。在指导阶段在 Andrew Gow 博士的实验室获奖，我将研究铜对表型分化的影响在永生化 BV-2 和原代小胶质细胞培养物中。特别是，我将研究铜如何改变关键- 信号分子和 S-亚硝基化谱响应急性毒素挑战以及如何铜的存在可能会干扰适应性炎症表型的采用。独立者奖励阶段将建立在指导阶段获得的调查结果的基础上。在这个阶段我会研究慢性铜超载对特定大脑解剖结构中小胶质细胞表型变化的影响 tx j 小鼠响应全身 LPS 挑战的结构。慢性铜超载的影响将还需要研究对小胶质细胞表型的影响是永久性的还是可能的去除多余的铜后反转。