NGF RECEPTOR REGULATION OF PROSTATE GROWTH

人类前列腺生长的异常调节是导致 与BPH和其他形式相关的大部分发病率和死亡率 老年男性前列腺肿瘤的发病率 在某种程度上， 前列腺的生长是由旁分泌/自分泌介导的 NGF与其同源高亲和力TrkA受体之间相互作用， 低亲和力神经生长因子受体（LNGFR）。 因此，根据我们先前的 已发表的著作以及其他初步研究 本文报道，我们建议测试的假设，这两种类型的 在NGF受体中，TrkA和LNGFR刺激和抑制生长， 分别在人前列腺上皮细胞中。 研究来支持 提出这一假设有三个具体目标。 第一特定 目的是表征Trk家族成员TrkA、TrkB 和TrkC在正常、BPH和肿瘤病理性前列腺中的表达， 原位杂交和免疫组织化学。 差异表达 这些Trk家族成员的发病率将与 前列腺与增殖细胞核抗原（PCNA）增殖 指数. 以这种方式，Trk表达的变化可以被调节。 与前列腺的生长速度和病理学有关。 第二 特定的目标将直接测试假定的生长刺激作用 通过用双稳定Tet-On转染TrkA受体 诱导型表达系统，其中多西环素用于调节 前列腺上皮细胞系中TrkA过表达水平。 的 TrkA的诱导过表达将根据 这些细胞的生长。 第三个具体目标将直接考验 通过用一种新的细胞因子转染LNGFR， 双稳定Tet-On诱导表达系统，其中多西环素 用于调节前列腺中LNGFR再表达的水平 上皮细胞系 LNGFR的诱导再表达将是 评估这些细胞生长速率的变化， 涉及增殖和诱导程序性细胞死亡。 我们 研究已经确定了NGF受体作为靶点， 前列腺生长的临床扰动。 因此，I期临床 目前正在进行吲哚咔唑Trk拮抗剂的试验， 乔治城大学的前列腺异常生长治疗 医学中心 神经生长因子受体的全面调查， 人类前列腺应该广泛适用于我们对 神经生长因子介导的前列腺自分泌/旁分泌调节机制 生长并加速这些观察结果转化为临床 设置.

Aberrant regulation of growth of the human prostate is responsible for much of the morbidity and mortality associated with BPH and other forms of prostatic neoplasia in the aging adult male population. In part, growth of the prostate is mediated by the paracrine/autocrine interaction between NGF and its cognate high affinity TrkA receptor and the low affinity NGF receptor (LNGFR). Hence, based upon our prior published work in conjunction with additional preliminary studies reported herein, we propose to test the hypothesis that the two types of NGF receptors, TrkA and the LNGFR stimulate and inhibit growth, respectively, in human prostate epithelial cells. Studies to support this hypothesis are proposed as three specific aims. The first specific aim is to characterize expression of the Trk family members, TrkA, TrkB and TrkC in the normal, BPH and neoplastic pathologic prostate by in situ hybridization and immunohistochemistry. Differential expression of these Trk family members will be correlated with the pathology of the prostate and a proliferating cell nuclear antigen (PCNA) proliferation index. In this manner, changes in the expression of the Trks may be related to the rate of growth and pathology of the prostate. The second specific aim will directly test the putative growth stimulatory effects of the TrkA receptor by transfection with a double stable Tet-On inducible expression system in which Doxycycline is used to regulate the level of TrkA overexpression in a prostate epithelial cell line. The induced overexpression of TrkA will be evaluated in relation to the rate of growth of these cells. The third specific aim will directly test the putative growth inhibitory effects of the LNGFR by transfection with a double stable Tet-On inducible expression system in which Doxycycline is used to regulate the level of LNGFR re-expression in a prostate epithelial cell line. The induced re-expression of the LNGFR will be evaluated for changes in the rate of growth of these cells as it pertains to proliferation and induction of programmed cell death. Our studies have already identified NGF receptors as targets for the clinical perturbation of prostate growth. As a result, phase I clinical trials are currently underway with an indolocarbazole Trk antagonist for the treatment of aberrant prostatic growth at Georgetown University Medical Center. A comprehensive investigation of the NGF receptors in the human prostate should be broadly applicable to our understanding of the mechanism of NGF mediated autocrine/paracrine regulation of prostate growth and hasten the translation of these observations to the clinical setting.