Hierachy Within Environmental Regulons

描述(申请人提供)：由细菌病原体感染 仍然是全世界的一个主要健康问题。例如, 在过去的十年里，霍乱的发病率蔓延到了 比过去100年来发生的任何事情都要多。更好地理解 致病的分子基础可能为抗击细菌提供新的途径 感染。这项研究的目标是弄清 人类宿主内环境中的生理信号被转换为 控制该菌毒力基因表达的分子相互作用 感染细菌。要分析的模型系统是霍乱弧菌 ToxR毒力调节子，对于其中影响基因的一些参数 表达，以及许多调节基因和靶基因，是已知的和 有部分特征的。目标毒力基因包括tcp操纵子， TCP型霍乱弧菌上存在的ToxT和其他“ToxR激活”基因 致病岛，以及CTX操纵子上存在的一种溶源 噬菌体。调节子是由分布在 基因组，包括毒素RS、Aph.4、AphB、HNS和CRP，以及tcpPH和 毒素T基因存在于致病岛上。最近已经确定了 每个靶基因启动子都有多个调控子发挥作用。海流 提案侧重于目标推动者和监管机构的子集，以了解 这些调节因子如何在与生长条件信号的相互作用中发挥作用， 启动子，并与彼此共同控制基因表达。此外， 基因表达受影响的其他靶基因的识别 不在弧菌Tcp致病力内编码的调节蛋白 海岛将有助于更好地理解精确的化学和物理 正在被转化为毒力基因表达机制的反应。 毒力基因表达与调控反应之间的关联 调节细菌生理学代表了一种利用知识 进一步了解毒力基因的基础 监管。最后，监测毒力基因表达的新方法 在体外和体内，将提供一种手段来关联这两个事件，并 找出参与调控的其他基因。这些实验很可能 揭示新的毒力因子基因，可能被证明是有用的疫苗或 治疗靶点。对毒力基因表达的进一步了解将 也有助于开发在体内或体外调节它的方法 用于改进疫苗生产或过量生产毒力因子 结构分析。

DESCRIPTION (provided by the applicant): Infection by bacterial pathogens continues to be a major health concern throughout the world. For example, during the past decade the incidence of cholera spread to more areas of the globe than had occurred in the previous 100 years. A better understanding of the molecular bases of pathogenesis may provide new ways to combat bacterial infection. The goal of this research is to discern the mechanisms by which physiological signals in the environment within the human host are converted to molecular interactions that govern the expression of virulence genes of the infecting bacterium. The model system to be analyzed is the Vibrio cholerae ToxR virulence regulon, for which a number of parameters that influence gene expression, as well as many of the regulators and target genes, are known and partially characterized. The target virulence genes include the tcp operon, toxT, and other "ToxR activated" genes present on the Vibrio cholerae TCP pathogenicity island, as well as the ctx operon present on a lysogenic bacteriophage. The regulators are encoded by genes distributed around the genome, including toxRS, aph.4, aphB, hns, and crp, as well as the tcpPH and toxT genes present on the pathogenicity island. It has recently been determined that multiple regulators function at each target gene promoter. The current proposal focuses on a subset of target promoters and regulators to understand how these regulators function in an interaction with growth condition signals, the promoters, and with each other to control gene expression. In addition, the identity of additional target genes for which expression is influenced by the regulatory proteins that are not encoded within the Vibrio TCP pathogenicity island will help to better understand the precise chemical and physical responses that are being converted into virulence gene expression mechanisms. Correlating virulence gene expression together with regulatory responses that modulate bacterial physiology represents a new approach that utilizes knowledge of the genome to further our understanding of the basis of virulence gene regulation. Finally, new approaches to monitor virulence gene expression both in vitro and in vivo will provide a means to correlate these two events and to identify additional genes involved in regulation. These experiments will likely reveal novel virulence factor genes that may prove to be useful vaccine or therapeutic targets. A further understanding of virulence gene expression will also help in the development of ways to modulate it either in vivo or in vitro for improved vaccine production or overproduction of virulence factors for structural analyses.