? 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK075651-03
Application #
7478086
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2006-09-10
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$114,607
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Allam, Ayman B; von Chamier, Maria; Brown, Mary B et al. (2014) Immune profiling of BALB/C and C57BL/6 mice reveals a correlation between Ureaplasma parvum-Induced fetal inflammatory response syndrome-like pathology and increased placental expression of TLR2 and CD14. Am J Reprod Immunol 71:241-51
Vincent, Charles R; Thomas, Tami L; Reyes, Leticia et al. (2013) Symptoms and risk factors associated with first urinary tract infection in college age women: a prospective cohort study. J Urol 189:904-10
von Chamier, Maria; Allam, Ayman; Brown, Mary B et al. (2012) Host genetic background impacts disease outcome during intrauterine infection with Ureaplasma parvum. PLoS One 7:e44047
Allam, Ayman B; Alvarez, Sophie; Brown, Mary B et al. (2011) Ureaplasma parvum infection alters filamin A dynamics in host cells. BMC Infect Dis 11:101
Reyes, Leticia; Alvarez, Sophie; Allam, Ayman et al. (2009) Complicated urinary tract infection is associated with uroepithelial expression of proinflammatory protein S100A8. Infect Immun 77:4265-74
Reyes, Leticia; Reinhard, Mary; Brown, Mary B (2009) Different inflammatory responses are associated with Ureaplasma parvum-induced UTI and urolith formation. BMC Infect Dis 9:9