Self-propagating mechanism of prion diseases

描述（由申请人提供）：朊病毒疾病是一组致命的年龄依赖性神经退行性疾病，可以自发或遗传，但也可以是传染性的。新朊病毒株自发出现和大流行传播的可能性以及现有株向包括人类在内的新宿主的传播和适应性是公共卫生的重大关切。关于朊病毒如何在动物和人类中起源和进化的分子方面，或者朊病毒株进化的基本原理，人们知之甚少。朊病毒株表现出高水平的构象可塑性，并且在传播到新宿主时易于“突变”。具体目标1将调查朊病毒的发生和进化的机制，并测试新的假设，即传染性朊病毒疾病可以诱导淀粉样蛋白结构从根本上不同于PrPSc。具体目标2将利用我们实验室产生的朊病毒疾病的新模型，阐明导致临床朊病毒疾病的病理事件，并探索导致菌株特异性嗜神经性的因素。具体目标3将阐明机制负责朊病毒株'突变'和适应。具体而言，这一目标将测试是否在辅因子环境的朊病毒复制的变化导致一个稳定的变化PrPSc的属性和新的疾病表型和（ii）是否在辅因子环境的变化影响的命运朊病毒适应跨越物种的障碍。这项研究将在医学院的环境中进行，将利用PI开发的朊病毒疾病的新实验模型，并将利用与国际知名的朊病毒病理学专家的合作。完成后，这项研究的结果将为理解感染性蛋白质状态的发生和进化机制奠定基础，并改变我们对朊病毒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.