Modeling Pheromone Induced Plasmid and Drug Resistance Transfer

描述（由申请方提供）：粪肠球菌中信息素诱导的接合性pCF 10质粒转移与抗生素耐药性的传播有关，导致机会性肠球菌感染的发病机制。肠球菌信息素系统的复杂性和独特的功能在于所涉及的两种不同的细胞类型，与信息素仅用于同步单个细胞类型的群体的系统相反。宿主细胞染色体编码信号传导分子，而负责感测和响应信号传导分子的遗传元件位于可通过缀合转移的质粒上。在质粒转移到受体后，受体也接受质粒上的耐药基因并成为供体。当受体群体达到阈值密度并且信号分子（其也由供体细胞产生，因为其在染色体上编码）达到临界浓度时，发生缀合。随着接合的进行，受体细胞群逐渐变得与供体细胞“相同”。本申请旨在建立一个随机种群平衡模型，以阐明肠球菌质粒pCF10编码的接合系统的调控机制。为此，我们将首先为含有pCF10的细胞（供体细胞）开发确定性数学模型，以评估cCF10信息素系统的动力学和稳定性行为。随后，将开发考虑不同质粒拷贝数的供体和受体细胞并结合随机性的群体平衡模型，以更好地检查该信号系统在临床相关条件下的行为。将进行实验以量化参数并微调模型。这些模型将用于指导抗生素耐药性异化研究的实验设计。这项工作，通过采取系统的方法，并考虑人口分布和随机性，将引入一个新的角度对这个医学上重要的问题，并提供了很多深入了解接合抗生素耐药性转移的机制。

DESCRIPTION (provided by applicant): Pheromone-induced conjugative pCF10 plasmid transfer in Enterococcus faecalis is implicated in the transmission of antibiotic resistance contributing to the pathogenesis of opportunistic enterococcal infections. The complexity and the unique features of the Enterococcus pheromone system reside in the two distinct cell types involved, in contrast to systems in which pheromone merely acts to synchronize a population of a single cell type. The host cell chromosome encodes the signaling molecule while the genetic elements responsible for sensing and responding to the signaling molecule are on a plasmid that is transferable by conjugation. Upon the transfer of the plasmid to the recipient, the recipient also receives the drug resistance gene on the plasmid and becomes a donor. Conjugation occurs when the recipient population reaches a threshold density and the signaling molecule, which is also produced by the donor cell as it is encoded on the chromosome, reaches a critical concentration. As conjugation proceeds, the recipient cell population gradually becomes "identical" to the donor cell. This application aims to develop a stochastic population balance model to elucidate the regulatory mechanism of the conjugation system encoded by the enterococcal plasmid pCF10. To that end we will first develop a deterministic mathematical model for pCF10-containing cell (donor cell) to assess the dynamics and the stability behavior of the cCF10 pheromone system. Subsequently a population balance model which considers donors of different plasmid copy numbers and recipient cells and incorporates stochasticity will be developed to better examine the behavior of this signaling system under clinically relevant conditions. Experimentation will be carried out to quantify the parameters and fine tune the model. The models will be used to guide experimental design for investigation of the dissimilation of antibiotic resistance. The work, by taking a systems approach and considering population distribution and stochasticity, will introduce a fresh perspective on this medically important problem and provide much insight into the mechanism of conjugational antibiotic resistance transfer.