Molecular mechanisms of initiation of benign prostatic hyperplasia

项目总结/摘要 良性前列腺增生（BPH）是老年男性的一种进行性疾病，其特征在于： 前列腺尿道周围区域的增大。估计50%的男性有组织学证据 50岁时BPH的发生率为75%，80岁时为75%。BPH常伴有下尿路症状 （LUTS）。BPH很少致命，但可能导致严重危及生命的并发症，如急性尿潴留 如果不治疗的话。然而，BPH发生和发展的分子机制仍不完全 明白对这些机制缺乏了解是改善治疗的障碍。BPH是一种 由前列腺上皮和间质的非恶性增生引起的异质性疾病 隔间间质结节和上皮腺结节是BPH的两种典型结节。 间质结节与人胎儿前列腺间质的组织学比较显示， 胎儿前列腺基质的过程（从未成熟间充质表型到成纤维细胞的转变， 纤维肌型，最终是平滑肌型）在BPH的发展中重演 间质结节这一观察结果支持了胚胎“再觉醒”理论，该理论提出， 类似FGF的胚胎信号传导的再激活归因于这些间质结节的起始和进展。 腺结节的形成被认为是间质增生的结果， 基质-上皮相互作用。但是腺结节的潜在分子机制还不清楚， 明确定义。我们的初步研究表明，Wnt信号在前列腺基质细胞中是活跃的， 能够调节前列腺上皮干细胞活性。此应用程序的目标是使用组合 分子和细胞生物学方法，基因工程小鼠模型， 研究前列腺基质细胞中的Wnt信号在BPH中是如何改变的，以及它如何影响 BPH发病机制。

Project Summary/Abstract Benign prostatic hyperplasia (BPH) is a progressive condition in aging men that is characterized by the enlargement of the periurethral regions of the prostate gland. An estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. BPH is often accompanied by lower urinary tract symptoms (LUTS). BPH is rarely fatal, but may cause serious life-threatening complications such as acute urinary retention if left untreated. However, molecular mechanisms of BPH initiation and progression remain incompletely understood. The lack of understanding of these mechanisms is a barrier to improved treatment. BPH is a heterogeneous disease that results from nonmalignant proliferations of both the prostate epithelial and stromal compartments. The stromal nodules and the epithelial glandular nodules are the two typical nodules in BPH. Histological comparison of the stromal nodules with human fetal prostate stroma revealed that the ontogenetic processes of fetal prostate stroma (a transition from immature mesenchymal phenotype to fibroblastic, fibromuscular, and ultimately smooth-muscular phenotype) are recapitulated in the development of the BPH stromal nodules. This observation supports a theory of embryonic “reawakening”, which proposes that improper reactivation of embryonic signaling like FGFs attributes to initiation and progression of these stromal nodules. Formation of glandular nodules is suggested to develop as a result of stromal hyperplasia and deregulated stromal-epithelial interaction. But the underlying molecular mechanisms for glandular nodules have not been defined definitively. Our preliminary study shows that the Wnt signaling is active in prostate stromal cells and is capable of regulating the prostate epithelial stem cell activity. The goal of this application is to use a combination of molecular and cellular biological approaches, genetically engineered mouse models, and human BPH specimens to investigate how the Wnt signaling in prostate stromal cells is altered in BPH and how it affects BPH pathogenesis.