Interstitial cystitis (IC) is a chronic disease of the bladder. The etiology is obscure. The mucosa of the normal urinary bladder faces a relatively hostile environment, one that contains high levels of calcium and, frequently, pathogenic microorganisms. The transitional epithelium produces and maintains at its surface glycosaminoglycans and a continuous layer of mucous glycoproteins, whose presence may explain why the bladder surface is so resistant to these insults. The main hypothesis underlying the studies we propose is that the onset of IC is caused by injury to this defense barrier by toxins produced by infectious agents, via two possible mechanisms (1) direct effects on the function of epithelial cells and (2) effects mediated by cytokines produced in response to the infection. The importance of these two mechanisms is difficult to assess in vivo, since many of these agents act synergistically. Using epitheilial and fibroblast cell cultures we isolate from the urinary bladder and the ureter, we propose a carefully developed plan to begin sorting out mechanisms which are likely to be involved in the pathogenesis of IC. To achieve this goal, the effects of bacterial toxins and cytokines will be tested on several cell functions, including: ion transport; proteoglycan synthesis, secretion and spatial distribution; induction of expression of major histocompatibility complex class II; induction of cytokine production and cell proliferation. Finally, we will study possible synergistic mechanisms of action for these agents and """"""""crosstalk"""""""" mechanisms between epithelial cells and fibroblasts from the lower urinary tract. The potential therapeutic applications are immense and include infectious diseases and autoimmune diseases. The long term objective of the proposed project is to contribute the background necessary for the rational design of clinically useful therapeutic agents for [C.
| Hofman, C R; Dileo, J P; Li, Z et al. (2001) Efficient in vivo gene transfer by PCR amplified fragment with reduced inflammatory activity. Gene Ther 8:71-4 |
| Henderson, R A; Konitsky, W M; Barratt-Boyes, S M et al. (1998) Retroviral expression of MUC-1 human tumor antigen with intact repeat structure and capacity to elicit immunity in vivo. J Immunother 21:247-56 |
| Henderson, R A; Nimgaonkar, M T; Watkins, S C et al. (1996) Human dendritic cells genetically engineered to express high levels of the human epithelial tumor antigen mucin (MUC-1). Cancer Res 56:3763-70 |
| Elgavish, A (1993) Effects of Escherichia coli and E. coli lipopolysaccharides on the function of human ureteral epithelial cells cultured in serum-free medium. Infect Immun 61:3304-12 |
