Global regulation by mgr in S. aureus

描述(申请人提供)：金黄色葡萄球菌能够引起多种人类疾病。最近，由于机体对抗生素治疗的耐药性增加，它变得更加成问题。因此，迫切需要新的治疗方法。该菌的致病性可归因于其产生大量细胞表面相关和胞外毒力因子的能力。这些毒力决定因素受几个互不相连的全球调控基因的协调调控。最近，我们发现了一个新的基因座，MGR，它影响几个毒力因子的产生，其模式与迄今报道的其他系统不同。随后，我们使用遗传和分子方法来定位和克隆这个全球调控基因座。测序、基因特异性突变和互补分析证实，该基因是一个新的基因座。我们的数据还表明，MGRA很可能是该基因座上唯一需要在调控中使用的基因。在这个方案中，我们建议完成三个特定的目标：(I)通过研究MGRA基因的转录组织和分析MGRA基因的启动子区域来确定MGR基因的分子特征；(Ii)研究MGRA基因调控靶基因的机制，并利用微阵列技术寻找更多的靶基因；(Iii)研究与其他全球调控系统的相互作用和MGRA基因表达的调控。将使用各种遗传、生物化学和分子方法来实现这些目标。这项建议中概述的研究的成功完成将提供对经理层监管制度的进一步深入了解。这些新的认识无疑将有助于我们理解金黄色葡萄球菌的全球调控机制，这将进一步为开发新的治疗方法提供坚实的基础。

DESCRIPTION (provided by applicant): Staphylococcus aureus is capable of causing a wide range of human diseases. It has become more problematic recently due to increasing resistance of the organism to antibiotic treatment. New methods of treatment are therefore urgently needed. The pathogenicity of this organism could be attributed to its ability to produce a large number of cell surface-associated and extracellular virulence factors. These virulence determinants are coordinately regulated by several unlinked global regulatory loci. Recently, we have identified a novel locus, mgr, which affects the production of several virulence factors in a pattern distinct from other systems reported to date. We have subsequently employed genetic and molecular methods to map and clone this global regulatory locus. Sequencing, gene-specific mutation and complementation confirmed that the mgr was a novel locus. Our data also suggest that mgrA is most likely the only gene in this locus that is required in the regulation. In this proposal, we propose to accomplish three specific aims: (i) to molecularly characterize the mgr locus by studying the transcriptional organization and analyzing the promoter region of the mgrA gene; (ii) to investigate the mechanism of target gene regulation by mgr and to identify additional target genes by micorarray technology; (iii) to study interaction with other global regulatory systems and control of mgrA gene expression. Various genetic, biochemical and molecular approaches will be employed to accomplish these aims. The successful completion of the studies outlined in this proposal will provide further insights into the mgr regulatory system. The new knowledge will undoubtedly contribute to our understanding of global regulatory mechanism in S. aureus, which will further provide a solid basis for the development of new treatments.