ROLE OF NGF PEPTIDES AND RECEPTORS IN BPH

良性前列腺增生症(BPH)是由 成年男性的尿路梗阻。良性前列腺增生症的规范管理 包括经尿道前列腺电切术，以缓解 障碍物。每年有超过50亿美元花在 在北美治疗BPH，引起了人们对 治疗这种疾病的非手术方法。雄激素是 良性前列腺增生症的发展所需要的，然而，引发 并调节BPH在成人前列腺中的生长一直没有 得到充分的阐明。在此背景下，我们的实验室已经确定 由基质细胞分泌的神经生长因子(NGF)样肽，以及 在邻近的上皮细胞中有一个相应的受体系统 调节人类前列腺中旁分泌的交互生长。按顺序 为了进一步了解前列腺生长的调节 应用于BPH我们已经启动了对NGF样肽的研究，并 用细胞培养和器官培养研究人前列腺中的受体 具有BPH细胞系和组织的系统。具体地说，这项研究 提案包含三个主要目标。第一个具体目标是 为了研究类固醇的作用，已知的启动子和调节因子 BPH对细胞增殖和NGF样肽产生的影响 两个间质细胞系，其中一个来自BPH组织和 其他细胞系来自正常的人类前列腺组织。这个 第二个特异性目的是研究NGF样蛋白的表达 BPH组织中的受体。神经生长因子样肽与细胞相互作用 表面通过一个由75kD蛋白质组成的受体复合体 被认为可以调节140kD的磷酸酪氨酸激酶的活性 受体，它反过来在结合时介导信号转导 神经生长因子样肽。我们观察到要么缺乏，要么减少 受体复合体75kD调控组分在大肠杆菌中的表达 前列腺增生症组织。这导致了我们的假设，在BPH组织中存在缺陷 75kD蛋白的表达消除了140kD蛋白的调节 磷酸化酪氨酸激酶导致上皮细胞失控生长 细胞。为了研究这一假说，我们将进一步检验 75kD和14kD受体蛋白在微粒体中的表达 前列腺增生症组织的组分及其转录后表达 使用分子探针对140kD的磷酸酪氨酸激酶进行研究 用Northern杂交技术进行杂交。在第三个具体目标中，我们将使用器官 研究神经生长因子样细胞之间相互作用的培养技术 肽和类固醇在调节细胞间平衡中的作用 BPH组织中的增殖和细胞死亡。因此，通过使用CELL 培养、器官培养、内分泌、生化和分子 生物技术我们可能对NGF样蛋白的作用有新的见解 旁分泌的多肽和相应的受体复合体 基质细胞与上皮细胞间的相互作用 调控褐飞虱的生长。

Benign prostatic hyperplasia (BPH) is a major cause of morbidity from urinary obstruction in the adult male. The standard management of BPH involves transurethral resection of the prostate to alleviate the obstructions. Over 5 billion dollars per annum are expended on the treatment of BPH in North America, resulting in considerable interest in non-surgical methods for the treatment of the disease. Androgens are required for the development of BPH, however the factors which initiate and regulate the growth of BPH in the adult prostate have not been adequately elucidated. In this context, our laboratory has identified a nerve growth factor (NGF)-like peptide secreted by stromal cells, and a corresponding receptor system in the adjacent epithelial cells which regulates paracrine interactive growth in the human prostate. In order to further understand the regulation of the growth of the prostate as it applies to BPH we have initiated studies on the NGF-like peptide and receptors in the human prostate using cell culture and organ culture systems with BPH cell lines and tissue. Specifically, this research proposal contains three primary objectives. The first specific aim is to investigate the role of steroids, known promoters and regulators of BPH, on cell proliferation and the production of the NGF-like peptide in two stromal cell lines, one of which is derived from BPH tissue and the other cell line is derived from normal human prostate tissue. The second specific aim is to investigate the expression of NGF-like receptors in BPH tissue. NGF-like peptides interact with the cell surface through a receptor complex consisting of a 75 kD protein which is thought to modulate the activity of a 140 kD phosphotyrosine kinase receptor, which in turn mediates signal transduction upon the binding of the NGF-like peptide. We have observed either a lack or diminished expression of the 75 kD regulatory component of the receptor complex in BPH tissues. This has led to our hypothesis that in BPH tissue a defect in expression of the 75 kD protein eliminates modulation of the 140 kD phosphotyrosine kinase leading to uncontrolled growth of the epithelial cells. In order to investigate this hypothesis we will further examine the expression of the 75 kD and 14 kD receptor proteins in microsomal fractions of BPH tissue as well as the post-transcriptional expression of the 140 kD phosphotyrosine kinase using molecular probes which hybridize by Northern blot. In the third specific aim we will use organ culture techniques to investigate the interaction between the NGF-like peptide and steroids in modulating the balance between cell proliferation and cell death within BPH tissue. Hence, by using cell culture, organ culture, endocrinological, biochemical and molecular biological techniques we may gain new insights into the role of NGF-like peptides and the corresponding receptor complex in the paracrine interactions between stromal cells and epithelial cells during the regulation of BPH growth.