CONTROL OF PROSTATE-SPECIFIC GENE EXPRESSION

前列腺特异性基因表达的控制

• 批准号: 6381531
• 负责人: ROBERT J. MATUSIK
• 金额: $ 26.12万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381531
• 关键词: DNA binding protein; DNA footprinting; cell differentiation; developmental genetics; embryogenesis; gel mobility shift assay; gene expression; genetic promoter element; genetically modified animals; histogenesis; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory mouse; male; male castration; molecular cloning; prostate; reproductive development; transcription factor; western blottings

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.

随着成年的接近，前列腺经历了发育变化，从而导致青春期腺体成熟。 在此阶段，前列腺变成了一个分化的腺体，该腺产生了该物种繁殖和存活的蛋白质。 最近的两个人口趋势使对这些过程的理解位于最前沿。 男性生育能力的下降需要更好地理解正常的生殖发展，而衰老人口的增长需要更好地了解前列腺增长的进一步阶段，这通常会导致良性的前列腺增生和/或前列腺癌。 雄激素在前列腺的正常发育中起关键作用，但是，对于前列腺的器官测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，一个极小的探针蛋白启动子片段包含必要的调节信息，以靶向发育和前列腺上皮特异性基因表达与转基因小鼠的前列腺。 我们的假设是这些PB DNA序列可用于识别控制前列腺上皮细胞特异性基因表达的关键基因调节蛋白。 我们认为，确定控制前列腺特异性基因表达的这些关键调节蛋白将阐明控制前列腺的细胞测定和细胞分化的机制。 为了解读此Pb DNA片段中的信息，计划了以下特定目的：1）表征发育中的小鼠UGS中前列腺特异性探针素基因表达的个体发育； 2）确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； 4）确定在发育中的小鼠中这些前列腺特异性因素的表达模式。 最终目标是提供对前列腺上皮细胞基因表达的基本了解，这将导致对男性不育症的见识和导致前列腺疾病的机制。