Elucidating the Role of Biofilm-Forming Bacteria in Nephrolithiasis

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TITLE: Elucidating the Role of Biofilm-Forming Bacteria in Nephrolithiasis PROJECT SUMMARY/ ABSTRACT Kidney stone disease is common, affecting 11% of the US population. However, the pathogenesis of kidney stones is still not well understood. While 10% of stones are known to be infectious, calcium-based stones, which make up 80% of stones, have not previously been shown to associate with bacteria. However, recent publications have utilized next-generation sequencing to demonstrate bacterial infestation in calcium stones despite no evidence of prior or concurrent urinary tract infection in those patients. In preliminary work, we found that uropathogenic bacteria trigger increased calcium oxalate crystal growth compared to controls. We hypothesize that bacteria interact with calcium stones and promote the propagation of kidney stones. We further propose that this interaction involves the formation of bacterial biofilm. We will test these hypotheses using three specific aims: 1) To test the hypothesis that uropathogens initiate biofilm formation in stones 2) To test the hypothesis that known surface sensing pathways of Pseudomonas spp. and E coli trigger kidney stone formation and 3) To test the hypothesis that bacteria play an important role in triggering crystallization and crystal aggregation in urine-specific environments using an in vitro three-dimensional kidney model. These aims will be accomplished by utilizing multiple imaging and complementary techniques including Raman spectroscopy and x-ray fluorescence as well as single-cell tracking analyses and molecular genetic techniques to investigate biofilm initiation. This study will provide new insights into the role of bacteria in the propagation of calcium-based kidney stones. It will also facilitate the advancement of my independent biomedical researcher career. I will collaborate with and obtain guidance and tutelage from highly successful, experienced mentors who are committed to my professional development. My research capabilities will be augmented by didactic and hands-on training in microbiology, machine learning, and high-resolution imaging, thus preparing me with the tools necessary to transition to full independence as a surgeon-scientist. Lastly, this funding will allow me to contribute to elucidating the etiology of nephrolithiasis and will directly enable provide the preliminary data for my first R01 application.