MT VET COBRE PROJECT 4: ROLE OF COPPER IN PRION DISEASES

MT VET COBRE 项目 4：铜在朊病毒疾病中的作用

• 批准号: 7382193
• 负责人: Michele Ann McGuirl
• 金额: $ 22.67万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382193
• 关键词: MT; VET; COBRE; PROJECT; ROLE

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. Prion diseases are fatal neurodegenerative diseases of mammals and include Creutzfeld-Jacob disease (humans), scrapie (sheep), chronic wasting disease (elk, deer), and mad cow disease (cattle). These illnesses are characterized by the accumulation of misfolded prion protein (PrP), in the central nervous system. It is well known that the normal form of PrP (alpha-PrP) binds copper(II) at several sites within the N-terminal domain. Although the details of metal coordination and relative affinities for copper at these sites are not completely understood, a consensus view is emerging that alpha-PrP is able to bind up ~5 mononuclear copper(II) ions. In contrast, little is known about the copper environments in misfolded PrP, despite the indications that copper plays a role in this and other amyloid diseases. The PI¿s expertise in metallo-enzymes provides a unique perspective to elucidate the details of copper binding in misfolded /infectious PrP, and its effect on the conversion of normal protein to the diseased state. This information will help unravel the mechanism of prion propagation and infectivity. Dr. McGuirl's lab is investigating metal ion binding to various isoforms of recombinant PrP using biophysical techniques, including fluorescence and electron paramagnetic resonance (EPR) spectroscopies, isothermal titration calorimetry (ITC), and inductively coupled plasma-mass spectrometry (ICP-MS). In contrast with some published reports, we see no evidence for a high affinity copper(II) binding site within the C-terminal half of alpha-PrP. Studies of the other isoforms, including infectious PrP, are ongoing.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。朊病毒疾病是哺乳动物的致命性神经退行性疾病，包括克雅氏病（人类）、羊瘙痒病（绵羊）、慢性消耗性疾病（麋鹿、鹿）和疯牛病（牛）。这些疾病的特征是错误折叠的朊蛋白（PrP）在中枢神经系统中的积累。 众所周知，PrP的正常形式（α-PrP）在N-末端结构域内的几个位点结合铜（II）。虽然在这些网站上的金属配位和铜的相对亲和力的细节还没有完全理解，一个共识的观点是，α-PrP是能够绑定5单核铜（II）离子。相反，很少有人知道的铜环境中错误折叠的PrP，尽管有迹象表明，铜在这种和其他淀粉样疾病中发挥作用。PI在金属酶的专业知识提供了一个独特的视角来阐明错误折叠/感染性PrP中铜结合的细节，及其对正常蛋白质转化为疾病状态的影响。这些信息将有助于揭示朊病毒的传播和感染机制。 McGuirl博士的实验室正在使用生物物理技术研究金属离子与重组PrP的各种亚型的结合，包括荧光和电子顺磁共振（EPR）光谱，等温滴定量热法（ITC）和电感耦合等离子体质谱法（ICP-MS）。与一些已发表的报告相比，我们没有看到证据表明α-PrP的C-末端一半内有高亲和力的铜（II）结合位点。其他亚型的研究，包括传染性PrP，正在进行中。