MOLECULAR MECHANISMS OF HUMAN BLADDER CARCINOGENESIS

修订摘要：该计划项目资助的主要目标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，以进一步了解膀胱移行细胞癌的病因、诊断和预后。项目1将确定调控基因的从头甲基化在人类膀胱癌的发生和发展中的作用，并将研究吸烟和使用非类固醇抗炎药(NSAIDs)对异常甲基化模式的影响。项目2将确定COX-2和DNA甲基转移酶在原发肿瘤中的表达作用，并将表达水平与吸烟和非甾体抗炎药使用的暴露水平联系起来。项目3将确定细胞周期调控基因的表达变化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2中研究的基因编码的蛋白质的表达，长期目标是开发更好的技术来预测和建立更好、更合理的治疗方法。该计划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，到流行病学，再到与临床相关的翻译问题，如化学预防、复发风险预测和治疗反应。 这些目标的实现将得到三个核心设施的协助，包括一个行政核心、一个生物统计和膀胱癌数据库核心和一个病理学核心。计划项目赠款的目标将通过将研究实验室与参与将要进行的大多数实验的主要研究人员的办公室紧密地并列在一起而进一步实现。参与的研究人员在膀胱癌领域的转化研究领域有相当多的合作历史，这些互动将通过这项计划项目拨款得到正式和加强。

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.