PUI RESEARCH-ALCORN-PIVA

PUI 研究-ALCORN-PIVA

• 批准号: 7610229
• 负责人: MARTA PIVA
• 金额: $ 17.83万
• 依托单位: UNIVERSITY OF SOUTHERN MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610229
• 关键词: Alzheimer' s Disease; Cell Death; Cell Respiration; Computer Retrieval of Information on Scientific Projects Database; Cytoplasm; Data; Funding; Glutathione; Goals; Grant; Homeostasis; Institution; Ions; Literature; Metals; Mitochondria; Neurodegenerative Disorders; Neurons; Organelles; Pathogenesis; Pathway interactions; Phase; Physiological; Research; Research Personnel; Resources; Saccharomyces cerevisiae; Source; Superoxide Dismutase; Toxic effect; United States National Institutes of Health; Yeast Model System; base; catalase; extracellular; mitochondrial dysfunction; mutant

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term objective of this project is to elucidate the relationship between the mitochondria and the homeostasis of essential metal ions. The overall goal of the present phase of this project is to determine the underlying mechanisms of Cu2+ toxicity when mitochondria are dysfunctional in Saccharomyces cerevisiae. We have found a mutant with abnormal mitochondrial function that is hypersensitive to Cu2+. Based on these observations, we hypothesize that this mutant is unable to store Cu2+ inside the organelle when the extracellular levels equal 1 mM or higher. Thus, Cu2+ remains in the cytoplasm generating enough reactive oxidative species (ROS) to overwhelm the physiological detoxifying pathways (i.e.: catalase, superoxide dismutase, glutathione, metallothioneins etc.). Unchecked ROS then oxidizes essential cellular components, causing cell death. No data in the literature identifies mitochondrial abnormalities as the cause of Cu2+ toxicity or the ability of Cu2+ to generate cytoplasmatic ROS under severely reduced aerobic metabolism which are major gaps in understanding the pathogenesis of Alzheimers disease (AD). We aim to clarify the issue by using our experimental yeast model of Cu2+ toxicity due to mitochondrial dysfunction, which resembles the Cu2+-vulnerable neurons at the onset of this neurodegenerative disorder.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的长期目标是阐明线粒体与必需金属离子的稳态之间的关系。该项目本阶段的总体目标是确定当酿酒酵母中线粒体功能失调时，Cu2+毒性的潜在机制。我们发现一种具有异常线粒体功能的突变体对Cu2+过敏。基于这些观察结果，我们假设当细胞外水平等于1 mm或更高时，该突变体无法将CU2+存储在细胞器中。因此，Cu2+保留在细胞质中，产生足够的反应性氧化物种（ROS），以压倒生理排毒途径（即：过氧化氢酶，超氧化物歧化酶，谷胱甘肽，金属壳蛋白等）。未检查的ROS然后氧化了必需的细胞成分，从而导致细胞死亡。文献中没有数据将线粒体异常鉴定为Cu2+毒性的原因，或者在严重降低有氧运动代谢下产生细胞质ROS的能力，这是理解阿尔茨海默氏病（AD）发病机理的主要差距。我们旨在通过使用线粒体功能障碍引起的Cu2+毒性的实验性酵母模型来阐明该问题，该模型在这种神经退行性疾病的发作时类似于Cu2+可粘附的神经元。