Bladder inflammation is a common cause of severe discomfort and morbidity in patients. During bladder inflammation a bi-directional communication is established between nerves containing substance P (SP) and bladder mast cells. SP activates mast cells to release mediators. Reciprocally, mast cell products stimulate sensory nerves to release SP. This bi-directional communication creates a vicious cycle of bladder inflammation. In previous work, we reported that SP is spontaneously released within the bladder wall, activates neurokinin (NK) receptors, and is inactivated by peptidase such as neutral metalloendopeptidase (NEP). Nerve to mast cell communication is dramatically altered in the presence of urinary tract infection. E. coli endotoxin lipopolysaccharide (LPS) induces inflammation by activating mast cells and sensory nerves, and by decreasing NEP activity. The central hypothesis of this proposal is that, regardless of the cause (LPS, SP, or antigens), bladder inflammatory responses follow a common pathway which involves: activation of mast cells and sensory nerves, release of SP, activation of NK receptors, and modulation of NEP activity.
Three specific aims are proposed to test these hypothesis.
Aim I will investigate the role of NEP in cystitis using NEP knockout mice.
Aim II will investigate the role of NK1 receptors in cystitis using NK1-R knockout mice.
Aim III will determine the role of mast cells in cystitis using genetically mast cell-deficient mice. The role of the mast cells in bladder inflammation will be precisely defined by examining the response in mast cell deficient mice that have had their mast cell deficiency selectively repaired by the adoptive transfer of mast cells derived from the normal congenic and NK1-R knockout mice. These studies will identify and define the important mechanisms involved in bladder inflammation and provide new insights for developing treatment strategies for cystitis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG4-UROL (01))
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University of Texas Medical Br Galveston
Internal Medicine/Medicine
Schools of Medicine
United States
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Saban, Ricardo; Saban, Marcia R; Maier, Julie et al. (2008) Urothelial expression of neuropilins and VEGF receptors in control and interstitial cystitis patients. Am J Physiol Renal Physiol 295:F1613-23
Saban, Marcia R; Backer, Joseph M; Backer, Marina V et al. (2008) VEGF receptors and neuropilins are expressed in the urothelial and neuronal cells in normal mouse urinary bladder and are upregulated in inflammation. Am J Physiol Renal Physiol 295:F60-72
Saban, Marcia R; O'Donnell, Michael A; Hurst, Robert E et al. (2008) Molecular networks discriminating mouse bladder responses to intravesical bacillus Calmette-Guerin (BCG), LPS, and TNF-alpha. BMC Immunol 9:4
Saban, Marcia R; Towner, Rheal; Smith, Nataliya et al. (2007) Lymphatic vessel density and function in experimental bladder cancer. BMC Cancer 7:219
Saban, Marcia R; Hellmich, Helen L; Simpson, Cindy et al. (2007) Repeated BCG treatment of mouse bladder selectively stimulates small GTPases and HLA antigens and inhibits single-spanning uroplakins. BMC Cancer 7:204
Saban, Ricardo; Simpson, Cindy; Davis, Carole A et al. (2007) Transcription factor network downstream of protease activated receptors (PARs) modulating mouse bladder inflammation. BMC Immunol 8:17
Dozmorov, Mikhail G; Kyker, Kimberly D; Saban, Ricardo et al. (2007) Systems biology approach for mapping the response of human urothelial cells to infection by Enterococcus faecalis. BMC Bioinformatics 8 Suppl 7:S2
Saban, Ricardo; Simpson, Cindy; Vadigepalli, Rajanikanth et al. (2007) Bladder inflammatory transcriptome in response to tachykinins: neurokinin 1 receptor-dependent genes and transcription regulatory elements. BMC Urol 7:7
Saban, Marcia R; Simpson, Cindy; Davis, Carole et al. (2007) Discriminators of mouse bladder response to intravesical Bacillus Calmette-Guerin (BCG). BMC Immunol 8:6
Saban, Ricardo; D'Andrea, Michael R; Andrade-Gordon, Patricia et al. (2007) Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation. BMC Physiol 7:4

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