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

描述（由申请方提供）：金黄色葡萄球菌是社区和临床环境中引起人类疾病的主要细菌病原体之一，具有显著的发病率和死亡率。最近出现的万古霉素和社区相关的耐甲氧西林S。金黄色葡萄球菌菌株进一步强调了新靶点鉴定对于开发新治疗剂的重要性。葡萄球菌的发病机制是一个复杂的过程，涉及多种毒力因子;因此，针对单一因子的有效治疗策略对这种生物体并不十分成功，这并不奇怪。为了应对抗生素耐药菌株的出现并通常靶向该生物体，有用的策略可以是单独或组合地破坏全局调节途径，以最小化体内细胞外和细胞表面相关因子的表达。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家族转录调节因子，因为它在葡萄球菌的遗传和发病机制以及葡萄球菌调控网络的控制中发挥着重要作用。这个基因家族被调节和调节其靶基因的精确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家族基因的调控以及由SarA家族蛋白调控的毒力因子。这种调节可以通过SarA蛋白的位点特异性结合或环境因素来实现。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。据报道，在体外与体内的差异存在于基因表达谱和器官特异性基因表达调控范例的给定基因。我们相信，一些sarA旁系同源物可能有差异的表达模式，在体内相比，在体外，并可能有重要的后果，毒力或感染过程。因此，我们建议确定sarA家族基因在小鼠感染模型中的参与和意义，并比较sarA家族基因在一种重要的临床菌株医院相关的MRSA COL中的体内和体外表达谱。这一建议的实验结果将非常有用的理解和开发SarA旁系同源物靶向治疗药物，以预防或治疗葡萄球菌感染。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家族转录调节因子，因为它在葡萄球菌的遗传和发病机制以及葡萄球菌调控网络的控制中发挥着重要作用。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，但它们的调控模式和参与毒力过程在很大程度上是未知的。因此，我们的主要目的是确定在体内的意义和感染过程中的sarA家族基因的表达。

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.