PATHOGENIC MECHANISMS OF IC

间质性膀胱炎(IC)是一种慢性膀胱疾病。这个 病因尚不清楚。正常膀胱的粘膜面对一种 相对恶劣的环境，一个含有大量钙的环境 而且，经常是病原微生物。移行上皮 在其表面产生并维持糖胺聚糖和一种 粘液糖蛋白的连续层，它的存在可以解释为什么 膀胱表面对这些侮辱很有抵抗力。主 我们提出的研究背后的假设是IC的发病 由毒素引起的对这种防御屏障的损伤 感染剂通过两种可能的机制：(1)直接作用于 上皮细胞的功能及(2)细胞因子介导的效应 是为应对感染而产生的。这两个因素的重要性 机制很难在体内评估，因为许多这样的药物 协同行动。利用附壁细胞和成纤维细胞培养 从膀胱和输尿管分离出来，我们建议谨慎地 制定计划，开始整理可能成为 参与了IC的发病机制。为了实现这一目标，其效果 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；主要基因表达的诱导 组织相容性复合体II类；细胞因子的诱导产生 和细胞增殖。最后，我们将研究可能的协同效应。 这些因素的作用机制和相互间的“串扰”机制 下尿路上皮细胞和成纤维细胞。这个 潜在的治疗应用是巨大的，包括传染性 疾病和自身免疫性疾病。该计划的长远目标 拟议的项目是提供必要的背景知识 合理设计临床有用的治疗药物。

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.