Tamm-Horsfali protein(THP) is urine's most abundant protein. Its function has remained unclear, despite extensive research for over a century. One of the hypotheses about its function has been that it acts as a host defense actor against urinary tract infection. We are one of two groups to create the first gene knockout mouse for THP. ? ? In PRELIMINARY STUDIES, THP-deficient mice have difficulty clearing bacteria from the urinary bladder. ? ? The SPECIFIC AIMS of this proposal are: ? ? AIM#1) To define and circumscribe the role of THP as a host defense factor against UTI a) To determine if THP (-/-) mice are more prone to cystitis (inflammation of urinary bladder) in comparison with THP (+/+) mice, after transurethral inoculation of E.coli. b) To determine if THP (-/-) mice are more prone to pyelonephritis (inflammation of kidneys) in comparison with THP (+/+) mice, after transurethral inoculation of E.coli. c) To determine if the severity of bladder and kidney infection in THP (-/-) mice is related to the specific type of fimbrial expression in E. coll. d) To determine if THP (-/-) mice are more prone to UTI with bacteria other than E co//r specifically Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus saprophyticus, Enterococcus fecaelis and Morganella morganii, as measured by bladder and kidney bacterial loads after transurethral inoculation. ? ? AIM#2) To determine the mechanism of THP affecting the susceptibility for UTI a) Effect of THP on bacterial clearance from bladder . b) Effect of THP on bacterial - urothelial cell interaction c) Effect of THP on bacterial-leukocyte interaction ? ? Significance: These studies will clarify the function of urine's most abundant protein and will provide new knowledge about a host defense mechanism against UTI. The findings will allow a better understanding of the pathogenesis of UTI, a common human illness. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068474-02
Application #
7173717
Study Section
Special Emphasis Panel (ZRG1-RUS-B (03))
Program Officer
Mullins, Christopher V
Project Start
2006-02-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
2
Fiscal Year
2007
Total Cost
$291,616
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Raffi, Hajamohideen S; Bates Jr, James M; Laszik, Zoltan et al. (2009) Tamm-horsfall protein protects against urinary tract infection by proteus mirabilis. J Urol 181:2332-8