Molecular mechanisms of initiation of benign prostatic hyperplasia

项目摘要/摘要 良性前列腺增生症(BPH)是老年男性的一种进行性疾病，其特征是 前列腺的尿道部周围区域增大。据估计，50%的男性有组织学证据 到50岁时BPH的发病率为75%，到80岁时为75%。良性前列腺增生症常伴有下尿路症状 (LUTS)。良性前列腺增生症很少是致命的，但可能会引起严重的危及生命的并发症，如急性尿液滞留。 如果不治疗的话。然而，BPH发生和发展的分子机制仍不完全。 明白了。缺乏对这些机制的了解是改进治疗的障碍。前列腺增生症是一种 由前列腺上皮和间质的非恶性增殖引起的异质性疾病 车厢。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，个体发育 胎儿前列腺间质的过程(未成熟间充质表型向成纤维细胞的转变， 纤维肌肉，以及最终的平滑肌肉表型)在BPH的发展过程中被概括 间质结节。这一观察结果支持了一种萌芽中的“再觉醒”理论，该理论认为 像FGFs这样的胚胎信号的重新激活归因于这些间质结节的启动和进展。 腺结节的形成被认为是间质增生和去调节的结果。 间质-上皮相互作用。但腺结节的潜在分子机制尚未得到证实。 明确地定义了。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，并且是 能够调节前列腺上皮干细胞的活性。此应用程序的目标是使用组合 分子和细胞生物学方法、基因工程小鼠模型和人类BPH 研究前列腺间质细胞Wnt信号在BPH中的改变及其影响的标本 BPH的发病机制。

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.