CONTROL OF PROSTATE-SPECIFIC GENE EXPRESSION

随着成年期的临近，前列腺经历了一个发育变化，导致该腺体在青春期成熟。 在这个阶段，前列腺变成一个分化的腺体，产生对物种繁殖和生存至关重要的蛋白质。 最近的两个人口趋势将对这些过程的理解置于首位。 男性生育力下降需要更好地了解正常的生殖发育，而日益老龄化的人口需要更好地了解前列腺生长的进一步阶段，这些阶段往往导致良性前列腺增生和/或前列腺癌。 雄激素在前列腺的正常发育中起着关键作用，然而，对前列腺的器官决定和细胞分化所需的其他基本分子事件知之甚少。我们已经表明，一个非常小的probasin启动子片段包含必要的监管信息，以针对发育和前列腺上皮特异性基因表达的转基因小鼠的前列腺。 我们的假设是，这些PB DNA序列可用于确定关键的基因调控蛋白，管理前列腺上皮细胞特异性基因表达。 我们相信，确定这些关键的调节蛋白，控制前列腺特异性基因表达将阐明的机制，控制细胞的决定和细胞分化的前列腺。 为了破译该PB DNA片段中的信息，计划了以下具体目标：1）表征发育中小鼠UGS中前列腺特异性probasin基因表达的个体发生; 2）鉴定决定前列腺特异性基因表达的PB启动子序列; 3）克隆与前列腺特异性序列相互作用的调节因子;和4）确定这些前列腺特异性因子在发育小鼠中的表达模式。 最终目标是提供前列腺上皮细胞基因表达的基本理解，这将导致对男性不育和导致前列腺疾病的机制的了解。

With the approach of adulthood, the prostate undergoes a developmental change that results in the maturation of that gland at puberty. At this stage, the prostate becomes a differentiated gland which produces proteins fundamental for reproduction and survival of the species. Two recent population trends place the understanding of these processes at the forefront. A decline in male fertility requires a better understanding of normal, reproductive development and an increasing aging population demands a better understanding of the further stages of prostatic growth that often leads to benign prostatic hyperplasia and/or prostate cancer. Androgen plays a key role in the normal development of the prostate however, little is known about the other basic molecular events that are required for organ determination and cell differentiation of the prostate. We have shown that an extremely small probasin promoter fragment contains the necessary regulatory information to target both developmental and prostatic epithelial-specific gene expression to the prostate of transgenic mice. Our hypothesis is that these PB DNA sequences can be used to identify the critical gene regulatory proteins that govern prostatic epithelial cell-specific gene expression. We believe that identifying these critical regulatory proteins which control prostate-specific gene expression will elucidate the mechanisms that control both cell determination and cell differentiation of the prostate. To decipher the information within this PB DNA fragment, the following specific Aims are planned: 1) to characterize the ontogeny of prostate-specific probasin gene expression in the developing mouse UGS; 2) to identify the PB promoter sequences that dictate prostate-specific gene expression; 3) to clone the regulatory factors that interact with the prostate-specific sequences; and 4) to determine the patterns of expression of these prostate-specific factors in the developing mouse. The ultimate goal is to provide a basic understanding of prostatic epithelial cell gene expression that will lead to insight in male infertility and the mechanism that lead to prostatic disease.