Self-propagating mechanism of prion diseases

描述(申请人提供)：Pron疾病是一组致命的与年龄相关的神经退行性疾病，可以自发发生或遗传，但也可以是传染性的。自然出现的可能性和新的病毒株的大流行传播，以及现有病毒株向包括人类在内的新宿主的传播和适应，都是公共卫生非常关注的问题。普恩病毒在动物和人类中如何起源和进化的分子方面，以及普恩病毒株进化的基本原理，人们知之甚少。Pron菌株表现出高度的构象可塑性，当传播到新的宿主时，很容易发生‘突变’。具体目标1将研究PrP的发生和进化机制，并验证新的假设，即可传播的Prion疾病可以由与PrPSc根本不同的淀粉样蛋白结构诱导。SPICAL AIMS 2将利用我们实验室产生的新的普恩病毒疾病模型，阐明导致临床普恩病毒疾病的病理事件，并探索导致菌株特异性神经趋向性的因素。具体目标3将阐明Pron菌株‘突变’和适应的机制。具体地说，这一目标将测试PrPSc复制的辅因子环境的变化是否导致PrPSc属性和新的疾病表型的稳定变化，以及(Ii)辅因子环境的变化是否影响PrPSc在跨越物种屏障时适应的命运。这项研究将在一所医学院的环境中进行，将利用PI开发的Pron疾病的新实验模型，并将利用与国际知名的Prion病理学专家的合作。一旦完成，本研究的结果将为理解感染蛋白状态的发生和进化机制奠定基础，并改变我们对PrP菌株适应和突变机制的理解。

DESCRIPTION (provided by applicant): Prion diseases are a group of fatal age-dependent neurodegenerative diseases that can arise spontaneously or be inherited, but can also be infectious. The possibility of spontaneous emergence and the pandemic spread of new prion strains and the transmission and adaptation of existing strains to new hosts including humans are of great concern to public health. Little is known about the molecular aspects of how prions originate and evolve in animals and humans or the principles that underlie the evolution of prion strains. Prion strains exhibit a high level of conformational plasticity and are prone to 'mutation' when transmitted to a new host. Specific Aim 1 will investigate the mechanism of prion genesis and evolution and test the new hypothesis that transmissible prion diseases can be induced by amyloid structures fundamentally different from that of PrPSc. Specific Aims 2 will take advantage of new models of prion diseases generated in our laboratory for elucidating the pathological events that lead to clinical prion disease and for exploring factors responsible for strain-specific neurotropism. Specific Aim 3 will elucidate mechanisms responsible for prion strain 'mutations' and adaptation. Specifically, this aim will test whether a change in the co-factor environment of prion replication leads to a stable change in PrPSc properties and new disease phenotypes and (ii) whether changes in the co-factor environment affect the fate of prion adaptation upon crossing the species barrier. This study will take place in the environment of a medical school, will exploit novel experimental models of prion diseases developed by the PI, and will take advantage of collaborations with internationally known experts on prion pathology. When accomplished, the results from this study will lay the groundwork for understanding the mechanisms of genesis and evolution of infectious protein states and transform our understanding of the mechanisms responsible for adaptation and mutation of prion strains.