Identification of prostate-specific regulation elements

描述(申请人提供)：由于前列腺癌和良性前列腺增生症等前列腺疾病在人类中的高发病率，促使人们对了解前列腺癌的生物学感兴趣。前列腺生物学的一个重要但鲜为人知的方面是前列腺内特定区域身份的分子基础。然而，前列腺生物学的这一方面是重要的，因为前列腺疾病是以高度区域性的方式发生的，前列腺癌主要是周围区的疾病，而良性前列腺增生症主要是移行区的疾病。同样清楚的是，前列腺癌的上皮区特异性识别和进展都受到来自前列腺间质的旁分泌信号的影响。近年来，小鼠已经成为了解前列腺生物学和模拟前列腺疾病的越来越重要的模型系统。前列腺特异性启动子和增强剂促进了这一领域的研究。然而，具有特征性的前列腺特异性启动子和增强子并不足以探索前列腺发育和疾病的所有方面。我们的初步研究已经建立了一种新的有效的方法来筛选在前列腺癌中以区域特异性方式指导基因表达的启动子和增强子元件。本提案目标1中描述的工作将使用这一新方法来识别和表征与两个基因相关的启动子和增强子元件，这两个基因在目前可用的启动子或增强子元件无法获得的前列腺细胞类型中表达。其中一个基因在前列腺前部和背部的上皮细胞中特异表达。第二个基因在前列腺基质细胞中表达。这项提案的目标2中描述的工作将使用新定义的调控元件来创建表达Cre重组酶的转基因小鼠品系，这些品系在目前可用的Cre转基因品系不包括的前列腺细胞类型中表达。

DESCRIPTION (provided by applicant): Interest in understanding the biology of the prostate gland is motivated by the high incidence in humans of prostatic diseases including prostatic adenocarcinoma and benign prostatic hyperplasia. One crucial but poorly understood aspect of prostate biology is the molecular basis for region specific identity within the prostate. Nevertheless, this aspect of prostatic biology is important because prostatic diseases occur in a highly region-specific manner with prostatic adenocarcinoma predominantly a disease of the peripheral zone and benign prostatic hyperplasia predominantly a disease of the transition zone. It is also clear that both epithelial region-specific identity and the progression of prostatic adenocarcinoma are influenced by paracrine signals from the prostatic stroma. In recent years, the mouse has become an increasingly important model system for understanding prostatic biology and modeling prostatic diseases. Prostate-specific promoters and enhancers have facilitated this area of research. However, the characterized prostate-specific promoters and enhancers are not adequate to explore all aspects of prostatic development and disease. Our preliminary studies have established a new and efficient method to screen for promoter and enhancer elements that direct gene expression in a region-specific manner in the prostate gland. Work described in Aim 1 of this proposal will use this new approach to identify and characterize promoter and enhancer elements associated with two genes that are expressed in prostatic cell types not accessible with currently available promoter or enhancer elements. One gene is expressed specifically in epithelial cells of the anterior and dorsal prostate. The second gene is expressed in prostatic stromal cells. Work described in Aim 2 of this proposal will use the newly defined regulatory elements to create lines of transgenic mice expressing CRE recombinase in prostatic cell types not covered by currently available CRE transgenic lines.