BLRD Research Career Scientist Award Application

项目摘要 在我的高级研究职业科学家（SRCS）奖的竞争性更新中，我将继续我的研究， 服务和教学/辅导工作，这是过去资助期间的重点领域。 我的研究项目主要集中在抗生素耐药性，因为现在人们认识到， 逃避抗生素作用的病原体是目前对全球公共卫生的最重要威胁之一。 自1987年进入VA医学研究服务以来，我的研究计划一直是了解 细菌对抗菌剂产生耐药性的分子基础，其最终目标是提高基础 科学知识来改善人类健康。作为一个模型系统，实验室主要使用人类 性传播病原体淋病奈瑟菌，因为这种病原体历史上已经产生了耐药性 每一种抗生素，已进入临床实践，并具有显着的能力，以避免行动， 多主机防御系统我们的研究重点对退伍军人/现役军人和 美国每年报告的淋病病例超过55万例， 超过50%的N.淋病分离株对一种或多种抗生素具有抗性。此外，全世界估计 病例接近1亿，报告了对一线抗生素（阿奇霉素）耐药的菌株 和/或头孢曲松）。我的实验室的一个主要成就是发现， 抗生素耐药性，包括多药外排泵，药物渗透性变化，由于改变， 外膜结构和内膜稳态可能与淋球菌的能力有关， 逃避宿主防御介质并在实验感染期间存活。于是，我就先走了。 抗生素耐药性和细菌发病机制不一定是独立的实体， 一起学习。重要的是，我们的基础研究工作现在已经达到了一个点， 这些努力可以促进疫苗的开发和新抗生素的发现。除了这些研究工作，我 参与并领导了多个地方，国家和国际努力， 抗生素耐药性这些努力包括为期刊和研究部分提供广泛的同行评议服务， 国家和国际咨询委员会成员，促进新抗生素的开发， 通过指导NIH资助的博士前学生T32项目， 开发和指导研究生课程，并指导亚特兰大VA和埃默里的初级教师 大学医学院。这些广泛的努力加上我正在进行的富有成效的研究计划 将是我在下一个资助期内SRCS支持的工作重点。

Project Summary In this competitive renewal of my Senior Research Career Scientist (SRCS) award I will continue my research, service, and teaching/mentoring efforts that have been the areas of concentration during past funding periods. My research program focuses on antibiotic resistance as it is now recognized that the ability of bacterial pathogens to evade the action of antibiotics is now one of the most important threats to worldwide public health. My research program since entering the VA Medical Research service in 1987 has been to understand the molecular basis by which bacteria develop resistance to antimicrobials with the ultimate goal of advancing basic science knowledge to improving human health. As a model system, the laboratory has largely used the human sexually transmitted pathogen Neisseria gonorrhoeae since this pathogen has historically developed resistance to every antibiotic that has been brought into clinical practice and has a remarkable ability to avoid the action of multiple host defense systems. Our research focus is of importance to both the veteran/active military and civilian populations in the United States given that over 550,000 cases of gonorrhea are reported yearly with over 50% of N. gonorrhoeae isolates resistant to one or more antibiotics. Moreover, the worldwide estimate of cases approaches 100 million with reported instances of strains resistant to front-line antibiotics (azithromycin and/or ceftriaxone). A major accomplishment of my laboratory has been the finding that mechanisms of antibiotic resistance including multidrug efflux pumps, drug permeability changes due to alterations in outer membrane structure and inner membrane homeostasis can be linked to the ability of gonococci to evade mediators of host defense and survive during experimental infections. Thus, we advanced the concept that antibiotic resistance and bacterial pathogenesis are not necessarily separate entities and should be studied together. Importantly, our basic research efforts have now reached a point where translational-driven efforts can facilitate vaccine development and new antibiotic discovery. In addition to these research efforts, I have participated in and provided leadership for multiple local, national and international endeavors to combat antibiotic resistance. These efforts include extensive peer-review service for journals and study sections, membership on national and international advisory boards for agencies advancing new antibiotic development, teaching/mentoring programs through directing an NIH-funded T32 program for pre-doctoral students, developing and directing graduate level courses, and mentoring junior faculty at the Atlanta VA and Emory University School of Medicine. These extensive efforts coupled with my ongoing productive research program will be the focus of my SRCS-supported work during the next funding period.