INTEGRINS AND THE PATHOGENESIS OF INTERSTITIAL CYSTITIS

整合素与间质性膀胱炎的发病机制

• 批准号: 2147252
• 负责人: ADA ELGAVISH
• 金额: $ 15.29万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2147252
• 关键词: biological signal transduction; cell cell interaction; cell differentiation; cell growth regulation; collagen; estradiol; extracellular matrix; fibronectins; fluorescence microscopy; gene expression; hormone receptor; human tissue; immunofluorescence technique; immunoprecipitation; integrins; interstitial cystitis; laminin; molecular pathology; receptor binding; tissue /cell culture; transforming growth factors; urinary bladder epithelium

Interstitial cystitis (lC) is a chronic inflammatory disease of the urinary bladder. The etiology is obscure. One of the main diagnostic tools currently available for lC reveals the presence of glomerulations on cystoscopic examination. We propose that this and other symptoms associated with lC are indicative of aberrant ability for remodeling of the transitional epithelium, e.g. during micturition. The normal maintenance of tissue architecture involves the interaction of cells with extracellular matrix (ECM) and neighboring cells. Many of these interactions are mediated through integrins, a family of cell membrane ECM receptors. Integrins are of crucial importance in cell-cell signaling and in structural integrity at cell-cell junctions and cell-ECM interfaces. Based on preliminary studies in our laboratory, we propose the general hypothesis that dysregulation in expression, or spatial distribution, of specific integrins in bladder epithelial cells is an important etiological determinant of interstitial cystitis (lC). The main objective of the proposed studies is to investigate the role of integrins in cell-cell and cell-ECM interactions, and the regulation of their expression in urothelial cells. Epithelial cells we isolate from the human urinary bladder (UB) and human ureter (UT) will be studied using RNA analysis, immunoprecipitation studies, immunofluorescence microscopy, cell attachment and cell spreading assays, intracellular pH measurements by fluorescence spectroscopy, proliferation and differentiation assessment assays, with the following specific aims: (1) To investigate the constitutive expression of integrins involved in UB cell-cell contact and UB attachment to fibronectin (FN), collagen (CO), laminin (LN) and Matrigel; (2) To explore the possibility that transforming growth factor beta (TGFbeta and 17beta-estradiol regulate urothelial proliferation and differentiation by affecting integrin-mediated cell attachment, cell spreading or cell-cell contact; (3) To investigate whether ECM influences urothelial growth and differentiation by modulating intracellular signalling events via an integrin-mediated mechanism; (4) To investigate the possible influences of integrin expression and spatial distribution on phenotypic properties of urothelial cells from patients with lC and stress incontinence, including adhesion, production of FN, CO and LN, responsiveness to TGFbeta and 17beta-estradiol, differentiation and proliferation.

间质性膀胱炎（IC）是一种慢性炎症性疾病， 膀胱。病因不明。主要的诊断工具之一 目前可用的LC显示肾小球的存在， 膀胱镜检查。我们认为这种症状和其他症状 与lC相关的是指示重构的异常能力， 移行上皮，例如在排尿期间。正常 组织结构的维持涉及细胞与 细胞外基质（ECM）和邻近细胞。许多这些 相互作用是通过整合素介导的，整合素是细胞膜ECM的家族， 受体。整合素在细胞-细胞信号传导中至关重要， 在细胞-细胞连接处和细胞-ECM界面处的结构完整性。 根据我们实验室的初步研究，我们提出了一般的 假设在表达或空间分布失调， 膀胱上皮细胞中的特异性整合素是膀胱癌的重要病因 间质性膀胱炎（IC）的决定因素。的主要目标 提出的研究是研究整合素在细胞-细胞中的作用， 细胞-ECM相互作用，以及它们在细胞中表达的调节， 尿路上皮细胞我们从人类尿液中分离出上皮细胞 膀胱（UB）和人输尿管（UT）将使用RNA分析进行研究， 免疫沉淀研究，免疫荧光显微镜，细胞 附着和细胞铺展测定，通过 荧光光谱、增殖和分化评估 本研究的目的如下：（1）研究 参与UB细胞-细胞接触的整合素的组成型表达， UB与纤维连接蛋白（FN）、胶原蛋白（CO）、层粘连蛋白（LN）和 （2）探讨转化生长因子（TGF-β 1）在体外与人胚肺成纤维细胞（PBMC）共培养的可能性。 β（TGF β和17 β-雌二醇调节尿路上皮增殖， 通过影响整联蛋白介导的细胞粘附分化，细胞 （3）研究ECM是否影响细胞间的接触， 通过调节细胞内 通过整合素介导的机制的信号事件;（4）研究 整合素的表达和空间分布可能对 慢性炎症和应激患者尿路上皮细胞表型特征 失禁，包括粘连，FN、CO和LN的产生， 对TGF β和17 β-雌二醇的反应性，分化和 增殖