Structural Characterization of Prion Isoforms in Multiple TSE Diseases
多种 TSE 疾病中朊病毒亚型的结构特征
基本信息
- 批准号:8053786
- 负责人:
- 金额:$ 27.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmyloid ProteinsBovine Spongiform EncephalopathyBrainC-terminalCattleCharacteristicsChemicalsCreutzfeldt-Jakob SyndromeDetectionDeuteriumDiseaseElectron MicroscopyElectronsEnvironmentFamilyFatal Familial InsomniaGerstmann-Straussler-Scheinker DiseaseGleanGoalsHealthHumanHydrogenIndividualInheritedKuruLabelLengthMammalsMapsMass Spectrum AnalysisMembraneMembrane ProteinsMethodsModelingMolecular ConformationMutationN-terminalNatureNeurodegenerative DisordersPeptide FragmentsPrPSc ProteinsPrion DiseasesPrionsPropertyProtein IsoformsProtein SubunitsProteinsPublishingRecombinantsRelative (related person)ReporterResearchResolutionScrapieSeriesSheepSiteSpectrum AnalysisSpin LabelsStructureSurveysTechniquesTestingTissuesVariantVertebral columnWorkX-Ray Crystallographybasechronic wasting disease of elk and deercrosslinkdisease transmissioninterestmutantpreventprotein functionprotein misfoldingresearch studysolutesynucleintau Proteinstrend
项目摘要
DESCRIPTION (provided by applicant): The goal of this research is to elucidate the structure of the prion protein in its aggregated isoforms, and to elucidate the relationship between isoform structure and different types of prion diseases. Prion protein is the causative agent of many fatal neurodegenerative diseases of mammals. These diseases are characterized by the conversion of normal, monomeric prion protein (PrPC) to a misfolded conformational state that aggregates and accumulates as fibrillar plaques in the brain. Transmission of the disease can occur when one mammal ingests the infected tissue of another. When exposed to an infectious aggregate, normal PrPC takes on the misfolded conformation and the fibrils are thus propagated. Any treatment of a prion disease must prevent or abrogate misfolding/aggregation while not affecting normal PrP function. Hence, it is important to understand the structural differences between the PrP isofoms. High resolution structures of PrPC from many mammals have been determined by both NMR and X-ray crystallography. In contrast, the insoluble, fibrillar nature of the infectious form has hampered the elucidation of its structural details. However, numerous biophysical and spectroscopic studies suggest that the misfolded form contains a much higher proportion of ¿-sheet than normal PrP, which is mostly a-helical/random coil. This work will elucidate the nature of the PrP subunit interactions in several forms of recombinant PrP by using two biophysical techniques: site directed spin labeling (SDSL) combined with electron paramagnetic spectroscopy (EPR) and site directed crosslinking combined with mass spectrometry (MS). The EPR experiments provide information on protein backbone dynamics, secondary, tertiary, and quaternary structure, distances between labeled residues, and the mobility of the label itself. The crosslinking experiments will confirm the structural information gleaned from EPR. PUBLIC HEALTH RELEVANCE The elucidation of the details of the structure of prion fibrils will be of great value in developing treatments for prion diseases, which are fatal neurodegenerative diseases of mammals. These include Creutzfeldt-Jakob disease (CJD) and variant CJD, Gerstmann- Straussler-Scheinker disease, Fatal Familial Insomnia, and kuru (humans), scrapie (sheep), chronic wasting disease (elk, deer), and mad cow disease (cattle). Treatment of any prion disease must prevent or abrogate fibril formation while not affecting normal prion function; hence, it is important to understand the structural differences among the different prion isofoms.
描述(申请人提供):这项研究的目的是阐明Pron蛋白聚集型异构体的结构,并阐明异构体结构与不同类型的Pron疾病的关系。Prion蛋白是许多哺乳动物致死性神经退行性疾病的病原体。这些疾病的特征是正常的单体普鲁恩蛋白(PrPC)转化为错误折叠的构象状态,在大脑中聚集和积累为纤维斑块。当一种哺乳动物摄入另一种哺乳动物的受感染组织时,就会发生疾病的传播。当暴露在具有感染性的聚集体中时,正常的PrPC呈现错误折叠的构象,从而使纤维得以繁殖。在不影响PrP正常功能的前提下,任何PrP病的治疗都必须防止或消除错误折叠/聚集。因此,了解PrP异构体之间的结构差异是很重要的。许多哺乳动物的PrPC的高分辨结构已经通过核磁共振和X射线结晶学确定。相比之下,感染性形式的不溶性和纤维性阻碍了对其结构细节的阐明。然而,大量的生物物理和光谱研究表明,错误折叠的形式含有比正常PrP高得多的β-折叠,后者主要是a-螺旋/随机卷曲。这项工作将利用两种生物物理技术来阐明几种形式的重组PrP中PrP亚单位的相互作用:结合电子顺磁谱(EPR)的定点自旋标记(SDSL)和结合质谱学(MS)的定点定向交联法。EPR实验提供了关于蛋白质骨架动力学、二级、三级和四级结构、标记残基之间的距离以及标记本身的流动性的信息。交联实验将证实从EPR中收集到的结构信息。与公众健康相关对Pron纤维结构细节的阐明将对开发Pron疾病的治疗方法具有重要价值,Pron疾病是哺乳动物的一种致命的神经退行性疾病。这些疾病包括克雅氏病(CJD)和变异型CJD、Gerstmann-Straussler-Scheinker病、致死性家族性失眠和库鲁病(人)、瘙痒病(羊)、慢性消耗性疾病(麋鹿、鹿)和疯牛病(牛)。任何Pron病的治疗都必须在不影响Pron正常功能的同时防止或消除原纤维的形成;因此,了解不同Pron异构体之间的结构差异是很重要的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michele Ann McGuirl其他文献
Michele Ann McGuirl的其他文献
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{{ truncateString('Michele Ann McGuirl', 18)}}的其他基金
Structural Characterization of Prion Isoforms in Multiple TSE Diseases
多种 TSE 疾病中朊病毒亚型的结构特征
- 批准号:
8245069 - 财政年份:2008
- 资助金额:
$ 27.56万 - 项目类别:
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:
7721027 - 财政年份:2008
- 资助金额:
$ 27.56万 - 项目类别:
Structural Characterization of Prion Isoforms in Multiple TSE Diseases
多种 TSE 疾病中朊病毒亚型的结构特征
- 批准号:
7465238 - 财政年份:2008
- 资助金额:
$ 27.56万 - 项目类别:
Structural Characterization of Prion Isoforms in Multiple TSE Diseases
多种 TSE 疾病中朊病毒亚型的结构特征
- 批准号:
7591816 - 财政年份:2008
- 资助金额:
$ 27.56万 - 项目类别:
Structural Characterization of Prion Isoforms in Multiple TSE Diseases
多种 TSE 疾病中朊病毒亚型的结构特征
- 批准号:
7796834 - 财政年份:2008
- 资助金额:
$ 27.56万 - 项目类别:
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:
7610742 - 财政年份:2007
- 资助金额:
$ 27.56万 - 项目类别:
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 - 财政年份:2006
- 资助金额:
$ 27.56万 - 项目类别:
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
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