Determine the relative virulence and the temporal expression of sarA paralog gen

描述(申请人提供)：金黄色葡萄球菌是社区和临床环境中导致人类疾病的主要细菌病原体之一，具有相当高的发病率和死亡率。最近出现的万古霉素和社区相关的甲氧西林耐药金黄色葡萄球菌菌株进一步强调了新的靶点识别对开发新的治疗药物的重要性。葡萄球菌的发病机制是一个复杂的过程，涉及多个毒力因素；因此，针对单一因素的有效治疗策略对这种微生物并不是非常成功也就不足为奇了。为了应对抗生素耐药菌株的出现并从总体上针对这种微生物，一个有用的策略可能是单独或联合扰乱全球调控途径，最大限度地减少细胞外和细胞表面相关因子在体内的表达。为了了解葡萄球菌基因表达的调控与毒力的关系，我们将继续关注SARA家族的转录调控，因为它在葡萄球菌的遗传和发病机制中发挥核心作用，并控制葡萄球菌的调控网络。这一基因家族被调控和调控其目标基因的确切机制在很大程度上是未知的。我们的长期研究目标是了解葡萄球菌中SARA家族蛋白对SARA家族基因和毒力因子的调控。这种调节可以通过SARA蛋白的位点特异性结合或通过环境因素来完成。解释sar家族相关数据的一个关键障碍是，大多数结果来自体外研究。已有报道称，在特定基因的基因表达谱和器官特异性基因表达调控范式方面，体外和体内存在差异。我们认为，一些SARA同源病毒在体内的表达模式可能与体外的不同，并可能对毒力或感染过程产生重要影响。因此，我们建议确定SARA家族基因在小鼠感染模型中的参与及其意义，并比较医院相关临床分离株MRSA COL中SARA家族基因的体内和体外表达谱。这一建议的实验结果将对了解和开发SARA Paralog靶向治疗药物以预防或治疗葡萄球菌感染非常有用。公共卫生相关性：为了了解葡萄球菌基因表达的控制与毒力的关系，我们将继续关注SARA家族的转录调控，因为它在葡萄球菌的遗传和发病机制以及控制葡萄球菌的调控网络中发挥核心作用。葡萄球菌特异性SARA家族基因正在成为治疗干预的潜在靶点，但它们的调节模式和参与毒力过程在很大程度上是未知的。因此，我们这项建议的主要目的将是确定体内意义和SARA家族基因在感染过程中的表达。

DESCRIPTION (provided by applicant): Staphylococcus aureus is one of the major bacterial pathogens in both community and clinical settings causing disease in human with substantial morbidity and mortality. The recent emergence of vancomycin and community-associated methicillin resistance S. aureus strains has further highlighted the importance of new targets identification for the development of novel therapeutic agents. The pathogenesis of Staphylococcus is a complex process that involves multiple virulence factors; therefore, it is not surprising that an effective therapeutic strategy directed against a single factor has not been highly successful against this organism. To deal with the emergence of antibiotic resistant strains and to target this organism in general, a useful tactic may be to disrupt the global regulatory pathways, singly or in combination, to minimize the expression of extracellular and cell surface associated factors in vivo. To understand control of staphylococcal gene expression in relation to virulence, we will continue to focus on the SarA family transcriptional regulators because of its central role in staphylococcal genetic and pathogenesis and in control of the regulatory networks in Staphylococcus. The precise mechanism by which this family of genes is regulated and regulates their target genes is largely unknown. Our long-term research goal is to understand the regulation of sarA-family genes and virulence factors regulated by the SarA family proteins in Staphylococcus. This regulation can be accomplished by site-specific binding of SarA proteins or by the environmental factors. One key impediment to interpreting the sar-family related data is that a majority of results are derived from in vitro studies. It has been reported that in vitro vs. in vivo disparities exist in gene expression profiles and organ-specific gene expression regulatory paradigms for a given gene. We believe some of the sarA paralogs may have differential expression pattern in vivo as compared to that of in vitro and may have important consequences for virulence or infection processes. Therefore, we propose to determine the involvement and significance of sarA-family genes in mouse infection model and compare in vivo and in vitro expression profiles of sarA-family genes in one important clinical strain the hospital- associated MRSA COL. The experimental findings of this proposal will be very useful to understand and develop SarA paralogs targeted therapeutic agents to prevent or cure Staphylococcus infections. PUBLIC HEALTH RELEVANCE: To understand control of staphylococcal gene expression in relation to virulence, we will continue to focus on the SarA family transcriptional regulators because of its central role in staphylococcal genetic and pathogenesis and in control of the regulatory networks in Staphylococcus. Staphylococcal specific sarA family genes are emerging as potential targets for therapeutic intervention, but their mode of regulation and involvement in virulence process are largely unknown. Therefore, our major aims of this proposal will be to determine in vivo significance and the expression of sarA-family genes during infection process.