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Modeling Prion Dynamics

朊病毒动力学建模

基本信息

批准号：
8133673
负责人：
Suzanne Sindi
金额：
$ 4.31万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133673
关键词：
Accounting Adopted Affinity Animals Behavior Binding Biological Models Biology Bovine Spongiform Encephalopathy Cells Complex Computer Simulation Creutzfeldt-Jakob Syndrome Data Development Disease Dominant-Negative Mutation Drug Delivery Systems Ensure Eukaryota Event Generations Goals Growth Heterogeneity Human Kuru Life Link Mammals Masks Modeling Molecular Mutation Nature Neurodegenerative Disorders Nucleic Acids Organism Pathogenicity Pathway interactions Pharmaceutical Preparations Phenotype PrP Prion Diseases Prions Process Production Protein Conformation Protein Dynamics Proteins Research Resistance Role Scrapie Specific qualifier value Structure System Therapeutic Intervention Validation Work Yeasts base cell growth regulation conformer design fungus human disease in vivo mathematical model meetings models and simulation mutant physical state prion hypothesis protein misfolding sup35 therapeutic target three dimensional structure tool trait transmission process yeast prion

项目摘要

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.

描述（由申请人提供）：朊病毒假说提出了感染性和遗传性的新范例，其中正常细胞编码蛋白质的自我复制替代构象异构体指定了新特征。为了使蛋白质发挥这些过去仅限于核酸的作用，朊病毒蛋白必须经历物理状态和定位变化的多步骤途径，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异构体之间复杂的相互作用以及该过程的细胞调节。考虑到这些相互作用的动态性质以及多步骤朊病毒循环中事件的相互依赖性，开发可以在任何步骤修改的定量模型将作为预测工具，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体内繁殖的随机模型，并采用该模型来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主要干扰野生型蛋白的朊病毒繁殖的机制，这一过程将提供信息治疗靶点的合理设计。酵母系统中的实验易处理性（允许直接观察活细胞中的蛋白质构象和活性）与精确数学模型的开发相结合，为应对这些挑战提供了独特的机会。