朊病毒种属屏障分子机理的研究

Prion is a protein conformation based infectious agent, causing Transmissible Spongiform Encephalopathies (TSEs) in both human and animals. The prion protein (PrP) is a highly conserved glycoprotein, which is ubiquitously expressed in a variety of tissues with highest expression in the central nervous system. Convincing experimental evidence, including our most recent studies, strongly support that the infectious agent of TSEs is an aberrantly folded PrP, called PrPSc. Because of its unusual seeding capability, the pathogenic PrPSc isoform is able to seed normal cellular PrP into the PrPSc form, resulting in prion transmission. Although prion is an unusual infectious agent, prion transmission shares several characteristics with conventional infectious agents, such as the presence of a strong species barrier. The molecular mechanism of prion species barrier remains unclear. Here we propose to use mouse and hamster, two rodent prion models, to elucidate the molecular mechanism of prion species barrier. The mouse and hamster PrP molecules are almost identical, except for 11 mismatched amino acids. Despite the high sequence homology between mouse and hamster PrP molecules, a strong prion transmission barrier exists between mouse and hamster. We propose to analyze the influence of these mismatched amino acids using our recently developed recombinant prion propagation technique. In addition, the influence of these mismatched amino acids will also be verified using prion infected cell cultures. This comprehensive approach will help us to reveal the key structural features responsible for prion transmission, verify the "conformation selection" model and elucidate the molecular basis for prion species barrier. Knowledge gained from our proposed study will be extremely valuable for us to develop strategies to prevent the rare cross species prion transmission.

朊病毒是以变构的朊蛋白为信息传递载体的特殊病原体。朊病毒是如何导致种属屏障这一常规病毒的生物学特性是该领域存在的重大科学问题之一。本项目旨在研究小鼠朊病毒和仓鼠朊病毒间种属屏障的分子机理，拟以小鼠朊蛋白与仓鼠朊蛋白间差异的11个氨基酸为模型，运用朊病毒体外扩增（sPMCA）、朊病毒感染细胞等实验手段，阐明每个氨基酸对它们之间种属屏障的重要性。根据最近提出的"构象选择"理论，我们提出：每个不相同的氨基酸对小鼠与仓鼠之间的种属屏障具有不同的重要性，这一种属屏障能被不同的氨基酸突变组合所破除。该项目的顺利完成将有助于我们进一步了解朊病毒疾病的传播机理、传染性朊病毒结构上的关键点、验证"构象选择"理论、阐明朊病毒种属屏障的分子机制，并且这一成果将有助于我们防止特殊朊病毒株所导致的跨种属传播，预防如"疯牛病"般的突发公共卫生事件。

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