The overall goal of this proposal is to provide me with the skills and expertise necessary to launch my career in translational medical research in the field of urologic disease, particularly bacterial infections of the urinary tract. To achieve this goal, I will use the K01 mechanism to meet the following training objectives: Objective 1: Generate innovative data for publication in highly regarded peer-reviewed journals. Recurrent urinary tract infections (UTI) disproportionately affect women and are common, costly and sometimes life threatening. Escherichia coli is the most frequent causative agent of UTI, and has been shown in mouse models to establish antibiotic-resistant tissue reservoirs that persist long after acute infection of the bladder lumen is resolved. Bacterial emergence from such reservoirs has long been regarded as one likely origin of recurrent infections in humans. We have shown in a novel mouse model that Gardnerella vaginalis, a common member of the urogenital microbiota, causes E. coli to emerge from bladder reservoirs and initiate a recurrent UTI episode. The experiments outlined in this research plan test the hypothesis that G. vaginalis induces UTI recurrence by damaging the bladder epithelium (Aim 1) and modulating the host inflammatory response (Aim 2). These studies will increase our understanding of the mechanisms driving UTI recurrence and have the potential to identify G. vaginalis as a biomarker of risk in susceptible women. Objective 2: Gain expertise in performing translational research. I will engage in training activities, including seminars and didactic coursework offered by the NIH Clinical Center and through the Clinical Research Training Center (CRTC) of the Institute for Clinical and Translational Sciences (ICTS) at Washington University School of Medicine. This instruction will teach me the language and procedures of clinical study design and execution and is essential for me to meet my goal of leading a transdisciplinary team doing T1 clinical research. With guidance from my co-mentors and the Research Design and Biostatistics Group of the ICTS, I will hone my skills in this area by performing a nested case-control study that seeks to confirm the findings of our mouse model in human clinical specimens. Objective 3: Develop my professional abilities and grow my professional network. Washington University has a wealth of career development mechanisms offered through the Center for the Integration of Research, Teaching, and Learning, the Offices of Postgraduate and Faculty Affairs and the CRTC. I will attend seminars and courses on research ethics, scientific manuscript and grant writing, academic job interviewing, laboratory finances and management. Additionally, I will attend instructive seminars at national meetings on urology and infectious diseases, where I will present my research findings and network and build collaborative relationships with leading researchers in the field. I have assembled a mentoring committee that includes leaders in the field of UTI research, which will evaluate the completion of both my scientific and career development milestones and facilitate my transition to an independent investigator.
Recurrent urinary tract infection (rUTI) is a common and costly clinical problem, affecting millions of women in the U.S. and worldwide. We have found that the bacterium Gardnerella vaginalis triggers rUTI. This project seeks to understand how G. vaginalis causes rUTI and to determine whether G. vaginalis could serve as a biomarker of rUTI risk in women.
