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.
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|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|
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