Modeling Prion Dynamics

描述（由申请人提供）：朊病毒假说为感染性和遗传提出了一个新的范例，其中正常细胞编码蛋白质的自我复制替代构象指定了新的性状。为了使蛋白质发挥这些作用，这些作用在历史上仅限于核酸，朊病毒蛋白必须穿过物理状态和定位的多步变化途径，以确保替代构象异构体的持续产生，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该过程的细胞调控。鉴于这些相互作用的动态性质和多步骤朊病毒循环中事件的相互依赖性，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作。为此，我将开发一个朊病毒在体内传播的随机模型，并将该模型用于研究朊病毒生物学的两个方面，这两个方面对我们理解人类疾病有直接影响：朊病毒构象异构体或菌株之间的竞争，这与朊病毒疾病的种间传播有关，以及朊病毒结构域中的突变通过野生型蛋白质显性干扰朊病毒繁殖的机制，这一过程将为治疗靶点的合理设计提供信息。在酵母系统中的实验易处理性的组合，它允许直接观察蛋白质构象和活性在活细胞中，和一个准确的数学模型的发展提供了一个独特的机会，以满足这些挑战。

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.