PATHOGENIC MECHANISMS OF IC

间质性膀胱炎（IC）是一种慢性膀胱疾病。 的 病因不明。 正常膀胱的粘膜面对一个 相对恶劣的环境，一个含有高水平的钙 以及病原微生物。 移行上皮 在其表面产生并保持糖胺聚糖， 连续的粘液糖蛋白层，其存在可以解释为什么 膀胱表面对这些损害具有很强的抵抗力。 主要 我们提出的研究假设是，IC的发病是 由细菌产生的毒素对这种防御屏障的伤害引起的 感染因子，通过两种可能的机制（1）直接影响 上皮细胞的功能和（2）细胞因子介导的作用 是对感染的反应。 这两个的重要性 机制难以在体内评估，因为这些药物中的许多 协同行动。 使用上皮细胞和成纤维细胞培养， 分离膀胱和输尿管，我们建议仔细 已制定计划，开始整理可能被 参与了IC的发病机制。 为了实现这一目标， 细菌毒素和细胞因子将在几个细胞上进行测试， 功能，包括：离子转运;蛋白多糖合成，分泌 和空间分布;诱导表达的主要 组织相容性复合物II类;诱导细胞因子产生 和细胞增殖。 最后，我们将研究可能的协同作用， 这些试剂的作用机制和“串扰”机制之间的 上皮细胞和成纤维细胞。的 潜在的治疗应用是巨大的 疾病和自身免疫性疾病。 的长远目标 拟议的项目是提供必要的背景， 合理设计临床上有用的治疗药物[C.

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.