Struvite stones account for only 2 to 15% of stones, but cause the greatest morbidity, with complications ranging from frequent stone recurrence, sepsis and renal disease. Patients with struvite calculi have clinical evidence of a profound inflammatory response. Thus, the inability of the host to moderate and dampen the inflammatory response may be a key critical component to susceptibility. We have developed an animal model of genetic susceptibility to struvite stone formation. When infected with the human pathogen U. parvum, susceptible F344 rats developed spontaneous struvite stones accompanied by severe epithelial changes in the bladder, a more intense inflammatory response, and increase urinary levels of GRO/KC (an IL-8 analog), IL-6, IL-1(, IL-18, IFN-(, and TNF-( than did other rat strains. Because of my previous training in laboratory animal medicine, I have substantial experience in the development of animal models. In order to shift my focus towards understanding the genetics of susceptibility to disease, I will need to gain expertise in genomics, bioinformatics, and computational biology. I have assembled a core interdisciplinary group of mentors chosen for their approaches in infectious diseases, pathology, computer data mining, and bioinformatics. The rodent model of ureaplasmal infection and stone formation has the potential to elucidate the host immune response during stone formation I hypothesize that in susceptible individuals, the underlying cause of struvite stone formation during urinary tract infection is a disruption of normal immune regulation. Because multiple genes, some of which are not intuitively obvious, may be involved in immune dysregulation and tissue remodeling events, the most comprehensive approach to understanding the pathogenesis of struvite stone formation is the use of global gene expression analysis along with a well- defined animal model of struvite stone formation. Using cutting edge technologies such as computational biology to determine macroscopically subtle but biologically critical elements of gene regulation, I will address the hypothesis by completion of the following specific aims: (1) Identify gene expression profiles in bladder tissues from experimentally-infected rats that differ in susceptibility to struvite stone formation, and (2) Elucidate the specific regulatory checkpoints that modulate the inflammatory response in susceptible and resistant animals.
