Modeling Prion Dynamics

描述（由申请人提供）：朊病毒假说为感染性和遗传提供了一种新的范式，其中正常细胞编码蛋白的自我复制替代构象指定了新的特征。为了使蛋白质发挥这些作用（历史上仅限于核酸），朊病毒蛋白必须通过物理状态和定位变化的多步骤途径，以确保替代构象的持续产生，从而确保相关表型的稳定性。朊病毒生物学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和多步骤朊病毒周期中事件的相互依赖性，可以在任何步骤修改的定量模型的开发将作为一种预测工具，可以设计和解释系统的实验操作。为此，我将建立一个朊病毒在体内繁殖的随机模型，并利用该模型研究朊病毒生物学的两个方面，这对我们对人类疾病的理解有直接的影响：与朊病毒疾病的种间传播有关的朊病毒构象或菌株之间的竞争，以及朊病毒结构域突变主要干扰野生型蛋白的朊病毒繁殖的机制，这一过程将为治疗靶点的基本设计提供信息。酵母系统中的实验可追溯性，可以直接观察活细胞中的蛋白质构象和活性，以及精确数学模型的发展，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.