PROSTATE GROWTH REGULATION BY ADRENERGIC RECEPTORS

良性前列腺增生症(BPH)是最常见的肿瘤 在美国影响男性的疾病。长期目标 这项建议的关键是了解发展背后的机制 良性前列腺增生症。在这种情况下，目前的提案旨在测试 儿茶酚胺启动前列腺间质的总体假说 成长。目前的数据表明，BPH最初是一种吻合口疾病， 启动事件是前列腺成纤维细胞和/或 平滑肌细胞，尽管个别因素(S)对此负责 这一过程仍不清楚。儿茶酚胺最近被证明可以 诱导多种细胞类型(包括大鼠前列腺)的有丝分裂 基质细胞)，以及来自培养的血管和心脏细胞的证据 儿茶酚胺与肥厚性和增生性疾病的关系 回应。此外，G蛋白偶联受体(如 作为肾上腺素能受体)可以汇聚地激活共同的有丝分裂原 酪氨酸激酶受体途径；该途径涉及激活 P21ras蛋白和丝裂原激活蛋白(MAP)激酶的 然后启动一系列与细胞生长和分裂有关的事件。 儿茶酚胺也被证明可以调节多肽生长因子。 在不同的细胞中生产，代表了另一种方法， 儿茶酚胺可以间接调节前列腺的生长 自分泌或旁分泌机制。在目前的提案中，第一个 目的：研究去甲肾上腺素(NE)在大鼠脑内的作用。 一种与前列腺间质增生症有关的生长因子 一种使用可生物降解的去甲肾上腺素释放颗粒的啮齿动物模型。一个平行的 去甲肾上腺素对人前列腺细胞有丝分裂作用的评价 基质细胞将在原发和稳定的前列腺上进行。 基质细胞系。第二个具体目标是检查体外效应。 NE对生长因子生产的影响，使用各种技术 包括核糖核酸酶保护实验和蛋白质印迹分析。第三 假说研究前列腺间质细胞的有丝分裂途径 去甲肾上腺素诱导的RAS和MAP激活的研究 对培养的前列腺基质细胞的刺激；肾上腺素能受体 参与这一途径的激活将被确定使用 亚型选择性拮抗剂。随后的实验将确定 参与有丝分裂反应的细胞内通路 表达编码Galpha和Gbetagamma亚基的多肽 已经在以前的实验中证明了解偶联G蛋白 受体有丝分裂途径。

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.