BLRD Research Career Scientist Award Application

沙门氏菌感染每年造成全球约300万人死亡。多药 从2011年到2013年，临床沙门氏菌的耐药性增加了一倍多。世界卫生 该组织将沙门氏菌列为全球12大抗生素耐药性细菌威胁之一 健康这项研究职业科学家奖的目标是继续努力， 沙门氏菌毒力的认识对开发新型抗生素抗多重耐药 细菌病原体 沙门氏菌和其他病原菌对抗生素的耐药性在很大程度上是由细菌的耐药性调节的。 核苷酸alarmone鸟苷四磷酸和DksA蛋白。这两种介质都与 RNA聚合酶的二级通道，调节中枢代谢途径的转录， 各种各样的毒力计划。我们将继续研究 鸟苷四磷酸和DksA调节沙门氏菌的转录程序。研究 职业科学家奖也将使我们能够开发新的抗生素，抑制DksA依赖 细菌转录DksA与RNA聚合酶二级通道的结合是竞争性的 与Gre转录延伸因子的结合。我们发现沙门氏菌需要Gre蛋白 毒力和这种革兰氏阴性杆菌对抗生素的抗性。我们计划描述 Gre因子促进细菌致病和抗生素抗性的分子机制。 这些研究项目在性质上是高度合作的，涉及科学互动， 退伍军人事务部东部科罗拉多医疗保健系统、亚特兰大退伍军人医疗保健系统和亚特兰大退伍军人医疗保健系统的调查人员说， 中心和退伍军人管理局安阿伯医疗保健系统。我打算继续培养 这些富有成效的合作。初级教员、研究生和博士后研究员的培训 也是这个研究职业科学家奖的重要组成部分。此外，在合作 与退伍军人事务部东部科罗拉多医疗保健系统的其他调查人员一起， 威斯康星州麦迪逊VA医疗中心，我们将继续指导有前途的CDA-2候选人， 从而帮助培养下一代杰出的退伍军人事务部科学家。

Salmonella infections are responsible for an estimated 3 million annual deaths worldwide. Multidrug resistance among clinical Salmonella more than doubled from 2011 to 2013. The World Health Organization has ranked Salmonella as one of the top 12 antibiotic resistant bacterial threats to global health. The goal of this Research Career Scientist Award is to continue with our efforts to apply our knowledge of Salmonella virulence to the development of novel antibiotics against multidrug resistant bacterial pathogens. Resistance of Salmonella and other pathogenic bacteria to antibiotics is in great part regulated by the nucleotide alarmone guanosine tetraphosphate and the DksA protein. Both of these mediators bind to the secondary channel of RNA polymerase, regulating transcription of central metabolic pathways and a variety of virulence programs. We will carry on our research on the molecular mechanisms by which guanosine tetraphosphate and DksA regulate Salmonella transcriptional programs. The Research Career Scientist Award will also allow us to develop novel antibiotics that inhibit DksA-dependent bacterial transcription. Binding of DksA to the secondary channel of RNA polymerase is in competition with Gre transcription elongation factors. We have found that Gre proteins are needed for Salmonella virulence and the resistance of this Gram-negative rod to antibiotics. We plan to characterize the molecular mechanisms by which Gre factors promote bacterial pathogenesis and antibiotic resistance. These research projects are highly collaborative in nature, involving scientific interactions with investigators at the Veterans Affairs Eastern Colorado Healthcare System, the Atlanta VA Medical Center and the Veterans Administration Ann Arbor Healthcare System. I plan to continue fostering these productive collaborations. Training of junior faculty, graduate students and postdoctoral fellows are also important components of this Research Career Scientist Award. Moreover, in collaboration with other investigators at the at the Veterans Affairs Eastern Colorado Healthcare System and Wisconsin-Madison VA Medical Center, we will continue mentoring promising CDA- 2 candidates, and thus help train the next generation of outstanding VA scientists.