Modeling Prion Dynamics

描述(申请人提供)：Prion假说为传染性和遗传性提出了一个新的范例，在这个范例中，正常的、细胞编码的蛋白质的自我复制的交替构象指定了新的特征。为了使蛋白质发挥这些历史上仅限于核酸的作用，Pron蛋白质必须经历物理状态和定位变化的多步骤途径，以确保交替构象的持续生产，从而确保相关表型的稳定性。Pron生物学中的一个主要挑战是了解同一细胞中同一蛋白质的不同构象之间的复杂相互作用以及这一过程的细胞调控。考虑到这些相互作用的动态性质和多步骤普恩循环中事件的相互依存关系，开发一个可以在任何步骤修改的定量模型将作为一种预测工具，其中可以设计和解释对系统的实验操纵。为此，我将开发一个体内Pron传播的随机模型，并将该模型应用于研究Prion生物学的两个方面，这两个方面对我们对人类疾病的理解有直接影响：Prion构象或菌株之间的竞争，这与Prion疾病的物种间传播有关，以及Prion结构域中的突变主要干扰通过野生型蛋白传播的Prion的机制，这一过程将为治疗靶点的合理设计提供信息。酵母系统中的实验可控性允许直接观察活细胞中的蛋白质构象和活性，而精确数学模型的开发为应对这些挑战提供了独特的机会。

DESCRIPTION (provided by applicant): The prion hypothesis poses a new paradigm for both infectivity and inheritance in which self- replicating alternate conformers of a normal, cellularly encoded protein specify new traits. In order for a protein to act in these roles, which have been historically limited to nucleic acids, a prion protein must traverse a multi-step pathway of changes in physical state and localization to ensure continued production of the alternate conformer and, thus, stability of the associated phenotype. A major challenge in prion biology is to understand the complex interplay between different conformers of the same protein in the same cell and the cellular regulation of this process. Given the dynamic nature of these interactions and the interdependency of the events in the multi-step prion cycle, development of a quantitative model that can be modified at any step would serve as a predictive tool in which experimental manipulations to the system could be designed and interpreted. Toward this end, I will develop a stochastic model of prion propagation in vivo and adapt this model to study two aspects of prion biology with direct implications for our understanding of human disease: the competition between prion conformers or strains, which has been linked to the interspecies transmission of prion diseases, and the mechanism by which mutations in the prion domain dominantly interfere with prion propagation by the wildtype protein, a process that will inform the rationale design of therapeutic targets. The combination of experimental tractability in the yeast system, which allows direct observations of protein conformation and activity in live cells, and the development of an accurate mathematical model provide a unique opportunity to meet these challenges.