PROSTATE GROWTH REGULATION BY ADRENERGIC RECEPTORS

肾上腺素能受体对前列腺生长的调节

• 批准号: 2676429
• 负责人: DAVID T PRICE
• 金额: $ 10.73万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-28 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2676429
• 关键词: G protein; adrenergic receptor; benign prostate hyperplasia; cell growth regulation; connective tissue cells; connective tissue stroma; enzyme activity; gene induction /repression; growth factor; growth factor receptors; guanine nucleotide binding protein; human tissue; laboratory rat; male; mitogen activated protein kinase; mitogens; norepinephrine; prostate; receptor binding; receptor expression; tissue /cell culture

Benign prostatic hyperplasia (BPH) is the most common neoplastic condition affecting males in the United States. The long term objective of the proposal is to understand mechanism underlying the development of BPH. Within this context, the current proposal is designed to test the overall hypothesis that catecholamines initiate prostate stromal growth. Current data suggests BPH is initially a stomal disease with the initiating event being proliferation of prostatic fibroblasts and/or smooth muscle cells, although individual factor(s) responsible for this process remain unknown. Catecholamines have recently been shown to induce mitogenesis in a number of cell types (including rat prostate stromal cells), and evidence from cultured vascular and cardiac cells implicates catecholamines in both hypertrophic and hyperplastic responses. Furthermore, activation of G-protein coupled receptors (such as adrenergic receptors) can convergently activate a common mitogenic pathway with tyrosine kinase receptors; this pathway involves activation of p21ras proteins and mitogen activated protein (MAP) kinases which then initiate a series of events involved in cell growth and division. Catecholamines have also been shown to regulate peptide growth factor production in various cells, representing another method whereby catecholamines could indirectly modulate prostate growth through an autocrine or paracrine mechanism. In the current proposal, the first specific aim investigates the potential role of norepinephrine (NE) as a growth factor involved in initiating prostate stromal hyperplasia in a rodent model using a biodegradable NE releasing pellet. A parallel evaluation of the mitogenic effects of NE on cultured human prostate stromal cells will be performed on both primary and stable prostate stromal cell lines. The second specific aim examines in vitro effects of NE on growth factor production, using a variety of techniques including RNase protection assays and western blot analysis. The third hypothesis examines mitogenic pathways in prostate stromal cells by investigating ras and MAP kinase activation in response to NE stimulation of cultured prostate stromal cells; adrenergic receptors involved in the activation of this pathway will be determined using subtype selective antagonists. Subsequent experiments will define intracellular pathways involved in the mitogenic response by transiently expressing peptides encoding for Galpha and Gbetagamma subunits, which have been shown in previous experiments to uncouple G-protein coupled receptor mitogenic pathways.

良性前列腺增生（BPH）是最常见的肿瘤 影响美国男性的状况。 长期目标 该提议的是了解开发的基础机制 BPH。 在这种情况下，当前的建议旨在测试 Catecholamines启动前列腺基质的总体假设 生长。 当前数据表明，BPH最初是一种疟疾疾病 启动事件是前列腺成纤维细胞的扩散和/或 平滑肌细胞，尽管个人因素是为此负责的 过程仍然未知。 儿茶酚胺最近被证明 在多种细胞类型中诱导有丝分裂发生（包括大鼠前列腺 基质细胞），以及来自培养的血管和心脏细胞的证据 暗示肥厚和增生的儿茶酚胺 回答。 此外，G蛋白偶联受体的激活（这种 作为肾上腺素能受体）可以收集激活常见的有丝分裂 酪氨酸激酶受体的途径；该途径涉及激活 p21ras蛋白和有丝分裂原活化蛋白（MAP）激酶的蛋白质 然后启动一系列参与细胞生长和分裂的事件。 儿茶酚胺也已显示用于调节肽生长因子 在各种单元中生产，代表另一种方法 儿茶酚胺可以通过一个间接调节前列腺的生长 自分泌或旁分泌机制。 在当前的提议中，第一个 具体目的调查了去甲肾上腺素（NE）的潜在作用 引发前列腺基质增生涉及的生长因子 使用可生物降解的NE释放颗粒的啮齿动物模型。 平行 评估NE对培养的人前列腺的有丝分裂作用 基质细胞将在主要和稳定的前列腺上进行 基质细胞系。 第二个特定目的检查体外效应 NE的生长因子生产，使用多种技术 包括RNase保护测定和Western印迹分析。 第三 假设检查了前列腺基质细胞中的有丝分裂途径 研究对NE的RAS和MAP激酶激活 刺激培养的前列腺基质细胞；肾上腺素能受体 参与该途径的激活将使用 亚型选择性拮抗剂。 随后的实验将定义 瞬时参与有丝分裂反应的细胞内途径 表达编码Galpha和Gbetagamma亚基的肽 已经在以前的实验中显示了脱离G蛋白耦合的 受体有丝分裂途径。