MOLECULAR MECHANISMS OF HUMAN BLADDER CARCINOGENESIS

摘要：本项目的主要目的是利用两个独特的、免费的医院和基于人群的膀胱癌数据库，进一步了解膀胱移行细胞癌的病因、诊断和预后。项目1将确定调节基因的从头甲基化在人类膀胱癌的发生和发展中的作用，并将检查吸烟和使用非甾体抗炎药（NSAIDs）对异常甲基化模式的影响。项目2将确定COX-2和DNA甲基转移酶表达在原发性肿瘤中的作用，并将表达水平与吸烟和使用非甾体抗炎药的暴露水平联系起来。项目3将确定细胞周期调控基因表达的改变如何在膀胱癌的发生和预后中发挥作用，并将检查项目1和项目2中研究的基因编码蛋白的表达，其长期目标是开发更好的预测技术，并建立更好、更合理的治疗方法。该项目将涵盖膀胱癌的广泛方面，从膀胱癌发生过程中的细胞和分子事件，通过流行病学，到临床相关的转化问题，如化学预防，复发风险预测和治疗反应。

Revised Abstract: The major goals of this Program Project Grant are to utilize two unique and complimentary hospital and population-based bladder cancer databases to further understand the etiology, diagnosis and prognosis of transitional cell carcinoma of the bladder. Project 1 will determine the role of de novo methylation of regulatory genes in the initiation and progression of human bladder cancer and will examine the effects of cigarette smoking and use of non-steroidal anti-inflammatory drugs (NSAIDs) use on the patterns of abnormal methylation. Project 2 will determine the role of COX-2 and DNA Methyltransferase expression in primary tumors and relate the expression levels to exposure levels of cigarette smoking and NSAID use. Project 3 will determine how the altered expression of cell-cycle regulatory genes plays a role in the genesis and prognosis of bladder cancer and will examine the expression of proteins encoded by genes studied in Projects 1 and 2, with the long-term goal of developing better techniques for predicting and for establishing better, more rational treatment. The Program Project will cover a wide range of aspects of bladder cancer, extending from cellular and molecular events during genesis of bladder cancer, through epidemiology, to clinically relevant translational issues such as chemoprevention, prediction of risk for recurrence and treatment response. The achievement of these goals will be assisted by three Core Facilities including an Administrative Core, a Biostatistics and Bladder Cancer Database Core and a Pathology Core. The goals of the Program Project Grant will be furthered by the close juxtapositioning of the research labs and the offices of the principal investigators involved in most of the experiments to be performed. The participating investigators have a considerable history of collaboration in the areas of translational research in the field of bladder cancer and these interactions will be formalized and enhanced by this Program Project Grant.