METAL IONS & PROTEIN STRUCTURE IN PROTEIN-FOLDING DISEASES

金属离子

• 批准号: 7722760
• 负责人: LISA M MILLER
• 金额: $ 5.7万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7722760
• 关键词: Address; Binding; Cell membrane; Complex; Computer Retrieval of Information on Scientific Projects Database; Copper; Disease; Fluorescence; Funding; Goals; Grant; Image; In Situ; Institution; Ions; Lead; Metal Binding Site; Metals; Neurodegenerative Disorders; Neurons; PrPSc Proteins; Prion Diseases; Prions; Protein-Folding Disease; Research; Research Personnel; Resources; Scrapie; Source; Structure; Synchrotrons; Tissues; United States National Institutes of Health; base; conformer; oxidation; protein structure

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. Transmissible spongiform encephalopathies are fatal neurodegenerative disorders characterized by the conversion of the normal prion protein (PrPC) into aggregates of its pathological conformer (PrPSc). The mechanism behind this structural conversion is unclear but recent studies have suggested that metal-binding is involved. The primary goal of this project is to correlate the in situ structure of prion proteins and metal-binding sites in scrapie using synchrotron-based infrared (IR) imaging and x-ray fluorescence (XRF) microprobe, respectively. To this end, we are addressing 3 specific aims: (1) How are the copper content and the PrPSc concentration correlated? Does PrPSc accumulate first, followed by decreased levels of copper? Or, does a reduction in copper concentration lead to the formation of PrPSc aggregates? (2) As the disease progresses, where do PrPSc aggregates accumulate in the tissue and how is the copper content distributed? Do the aggregates form within the neuron, or extracellularly? If they form within the neuron, are they associated with the cell membrane? (3) What is the oxidation state and structure of the metal-PrPC (and metal-PrPSc?) complex?

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 遗传性海绵状脑病是一种致命性神经退行性疾病，其特征是正常的普恩蛋白(PrPC)转化为其病理构象的聚集体(PrPSc)。这种结构转换背后的机制尚不清楚，但最近的研究表明，其中涉及金属结合。这个项目的主要目标是分别使用基于同步加速器的红外成像和X射线荧光(XRF)微探针来关联瘙痒病中Pron蛋白的原位结构和金属结合位置。为此，我们正在解决三个具体目标：(1)铜含量与PrPSc浓度之间是如何关联的？PrPSc会先积累，然后降低铜的水平吗？或者，铜浓度的降低是否会导致PrPSc聚集体的形成？(2)随着疾病的发展，PrPSc聚集体在组织中积累在哪里，铜含量是如何分布的？这些聚集体是在神经元内部还是在细胞外形成的？如果它们形成在神经元内，它们是否与细胞膜有关？(3)金属PrPc(和金属PrPSc)的氧化状态和结构是什么？复杂？