Identification of prostate-specific regulation elements

描述（由申请人提供）：对了解前列腺生物学的兴趣是由人类前列腺疾病（包括前列腺腺癌和良性前列腺增生）的高发病率激发的。前列腺生物学的一个关键但知之甚少的方面是前列腺内区域特异性身份的分子基础。然而，前列腺生物学的这一方面是重要的，因为前列腺疾病发生在一个高度区域特异性的方式与前列腺腺癌主要是一种疾病的外周带和良性前列腺增生主要是一种疾病的过渡区。同样清楚的是，上皮区域特异性身份和前列腺腺癌的进展受到前列腺间质的旁分泌信号的影响。近年来，小鼠已成为了解前列腺生物学和前列腺疾病建模的越来越重要的模型系统。前列腺特异性启动子和增强子促进了这一领域的研究。然而，特征化的前列腺特异性启动子和增强子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个新的和有效的方法来筛选启动子和增强子元件，直接基因表达的区域特异性的方式在前列腺。本提案的目标1中描述的工作将使用这种新方法来鉴定和表征与两种基因相关的启动子和增强子元件，所述两种基因在前列腺细胞类型中表达，而目前可用的启动子或增强子元件不可及。一种基因在前列腺前部和背部的上皮细胞中特异性表达。第二个基因在前列腺基质细胞中表达。本提案目标2中描述的工作将使用新定义的调控元件来创建在前列腺细胞类型中表达CRE重组酶的转基因小鼠品系，这些前列腺细胞类型未被当前可用的CRE转基因品系所涵盖。

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.