Molecular Mechanism of Prion Strain

朊病毒株的分子机制

• 批准号: 8107833
• 负责人: JIYAN MA
• 金额: $ 33.36万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107833
• 关键词: Accounting; Affect; Animals; Biochemical; Biological Assay; Brain; Clinical; Cultured Cells; Disease; Future; Generations; Health; Human; In Vitro; Inbreeding; Knowledge; Lead; Molecular; Molecular Conformation; Mus; Neurodegenerative Disorders; Phenotype; Physiological; PrP; PrPSc Proteins; Preparation; Prion Diseases; Prions; Property; Proteins; Recombinants; Research; Resistance; Role; Route; Specific qualifier value; System; Testing; Time; Variant; base; conformer; disease phenotype; in vitro Assay; in vivo; insight; intraperitoneal; neuropathology; particle; prevent; prion hypothesis; prion seeds; prion-based; protein misfolding cyclic amplification; recombinant PrP; research study; transmission process

DESCRIPTION (provided by applicant): The presence of multiple prion strains is a great challenge to the prion hypothesis, which postulates that the variations in the pathogenic PrP conformation, PrPSc, lead to the prion strain phenomenon. Recent advance in prion field reveals a key role of other physiological factor(s) in facilitating PrP conversion and generating prion infectivity. Our recent results showed that, in the presence of proper facilitating factors, the bacterially-expressed recombinant PrP can be converted into the infectious conformation causing bona fide prion disease in animals. This discovery strongly supports the prion hypothesis, highlights the important role of facilitating factors in prion conversion, and opens new avenues for prion research. We propose to use the de novo recombinant prion formation system to study the role of facilitating factors in enciphering prion strains. We will use the in vitro PrP conversion assay, biochemical characterization, animal bioassay, and histopathological analyses to investigate the relationship among facilitating factors, the infectious prion aggregates, and the prion strain phenomenon in the following three specific aims. In aim 1, we propose to determine whether transmission in outbred mice with a single recombinant prion preparation is capable of creating multiple prion strains. In aim 2, we will determine whether two biochemically different recombinant prions represent two different strains. In aim 3, we will test the hypothesis that distinct prion strains can be created in the presence of different facilitating factors. Results from these studies will provide us with insights into the molecular mechanism behind prion strain phenomenon, which is critically important in preventing cross-species transmission of these fatal neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Prion diseases are a group of infectious neurodegenerative diseases affecting both human and animals. The most important issue in prion research is to prevent the potential spread of prion disease from animal to humans. Prion strain phenomenon is intimately related to the cross species transmission, and therefore, our proposed study is highly relevant to human health. Furthermore, the knowledge generated from proposed studies may also lead to new strategies against these devastating and incurable diseases.

描述（由申请人提供）：多种朊病毒株的存在对朊病毒假说提出了巨大挑战，朊病毒假说假定致病性PrP构象PrPSc的变化导致朊病毒株现象。朊病毒领域的最新进展揭示了其他生理因素在促进PrP转化和产生朊病毒感染性中的关键作用。我们最近的研究结果表明，在适当的促进因子的存在下，细菌表达的重组PrP可以转化为感染性构象，导致真正的朊病毒疾病的动物。这一发现有力地支持了朊病毒假说，突出了朊病毒转化中促进因子的重要作用，并为朊病毒研究开辟了新的途径。我们建议使用从头重组朊病毒的形成系统，以研究在编码朊病毒株的促进因素的作用。我们将使用体外PrP转化试验，生物化学特性，动物生物测定，和组织病理学分析，以探讨促进因素之间的关系，感染性朊病毒聚集体，和朊病毒株现象在以下三个具体目标。在目标1中，我们建议确定是否在远交系小鼠与单一的重组朊病毒制剂的传输是能够创建多个朊病毒株。在目标2中，我们将确定两种生物化学上不同的重组朊病毒是否代表两种不同的菌株。在目标3中，我们将检验在不同的促进因子存在下可以产生不同的朊病毒株的假设。这些研究的结果将为我们提供深入了解朊病毒应变现象背后的分子机制，这对于防止这些致命的神经退行性疾病的跨物种传播至关重要。 公共卫生相关性：朊病毒疾病是一组影响人类和动物的传染性神经退行性疾病。朊病毒研究中最重要的问题是防止朊病毒疾病从动物传播到人类。朊病毒株现象与跨物种传播密切相关，因此，我们的研究与人类健康高度相关。此外，从拟议的研究中产生的知识也可能导致对这些毁灭性和不治之症的新战略。