GROWTH INHIBITORY EFFECT OF GOSSYPOL ON CANINE/HUMAN BPH

人类良性前列腺增生症(HBPH)是最重要的 中老年男性的疾病，其病因没有明确的定义。 毫无疑问，hBPH的发生和发展受多种因素的调控。 内分泌因素。因此，增加我们对hBPH的认识需要一个 涉及基础和临床研究的多学科方法。 我们将尝试通过利用这种方法来实现这一目标，在 一种合适的犬类模型的基础和临床研究将 为开发治疗良性前列腺增生症的新方法提供资金 病人。我们建议的理由是基于以下几点 假设和证据：1)睾丸雄激素不是唯一的 调节正常和增生性疾病生长的限制因素 CBPH和hBPH中的前列腺；2)细胞间的相互作用 前列腺间质和上皮成分在前列腺癌中起重要作用。 CBPH和hBPH患者前列腺增生症的发病和消退 前列腺间质细胞对治疗的抵抗力远高于 4)去势去雄激素。 CBPH不会完全抑制前列腺的生长和功能 间质成分；5)GP具有生长抑制作用和 不同物种前列腺组织中抗类固醇激素的作用 包括人类在内，因此GP能够减少类固醇 对上皮性和间质成分均有破坏性影响 经GP处理的动物。这些由GP引起的间质的剧烈变化 细胞对开发新的细胞具有重要的临床意义 CBPH和hBPH患者的治疗策略；以及6)证据 前列腺亚细胞器中糖蛋白的高特异性结合 表达新的前列腺蛋白的组织和鉴定 受GP和睾丸素的调节。我们建议的具体目标是 研究内容如下：1)采用体内和体外模型研究 实验诱导的cBPH对前列腺生长的调节；2)使用 体外模型研究上皮细胞和内皮细胞的功能差异 从手术切除的不同组织标本中制备基质细胞 HBPH的区域；3)评估前列腺癌退行性变的调节 去势和GP治疗后的自发性cBPH患者；4) 为良性前列腺增生症的临床试验制定新的治疗策略 患者根据基础研究产生的实验数据 由目标1、2和3完成。这项拨款申请结合了我们的 研究人员在生殖内分泌学、类固醇方面的专业知识 生化、细胞生物学和临床医学在评价GP AS中的应用 治疗良性前列腺增生症的潜在替代药物。

Human benign prostatic hyperplasia (hBPH) is one of the most important diseases in men of advancing age, its etiology is not clearly defined. Undoubtedly, the onset and progression of hBPH is regulated by multiple endocrine factors. Thus, increasing our understanding of hBPH demands a multidisciplinary approach involving both basic and clinical research. We will attempt to achieve this goal by utilizing such an approach, in which basic and clinical research of an appropriate canine model will provide for the development of novel therapeutic approaches for hBPH patients. The rationale for our proposal is based on the following hypotheses and evidence: 1) testicular androgens are not the sole limiting factor for regulation of the growth of normal and hyperplastic prostates in both cBPH and hBPH; 2) cellular interactions between the prostatic stromal and epithelial components play vital roles in the onset and regression of prostatic hyperplasia in both cBPH and hBPH; 3) resistance of prostatic stromal cells to treatment is much higher than that of epithelial cells; 4) deprivation of androgen by castration in cBPH will not completely suppress the growth and function of prostate stromal components; 5) GP possesses growth inhibitory and antisteroidogenic effects on prostate tissues in different species including humans and that GP is capable of reducing steroids thereby causing disruptive effects in both epithelial and stromal components of GP-treated animals. These drastic, GP-induced changes in the stromal cells have important clinical implications for developing new therapeutic strategies for cBPH and hBPH patients; and 6) evidence of high specific binding of GP in subcellular organelles of prostatic tissues and identification of new prostatic proteins whose expressions are regulated by GP and testosterone. The specific aims of our proposed study are: 1) to use in vivo and in vitro models to examine the regulation of prostate growth in experimentally induced cBPH; 2) to use in vitro models to investigate differential functions of epithelial and stromal cells prepared from specimens surgically removed from different regions of hBPH; 3) to evaluate the regulation of prostate regression in spontaneous cBPH patients after castration and GP treatment; and 4) to formulate new therapeutic strategies for clinical trails in hBPH patients based on experimental data generated from the basic research accomplished by aims 1, 2 and 3. This grant application combines our investigators' expertise in reproductive endocrinology, steroid biochemistry, cellular biology and clinical medicine in evaluating GP as a potential alternative agent for treatment of BPH.