Molecular Mechanisms of Initiation of Benign Prostatic Hyperplasia

 描述（由申请人提供）：良性前列腺增生是老年男性的一种进行性疾病，其特征是由于前列腺上皮和基质区室中的非恶性增生导致前列腺尿道周围区域增大。估计50%的男性在50岁时有BPH的组织学证据，75%在80岁时有BPH的组织学证据。BPH通常伴有下尿路症状（LUTS）。BPH很少致命，但如果不及时治疗，可能会导致严重的危及生命的并发症，如急性尿潴留。雄激素靶向疗法如非那肽在临床上用于治疗BPH。然而，MTOPS研究表明，即使使用芬达和多沙唑嗪的联合治疗也仅导致LUTS/BPH临床进展风险降低66%，这表明存在未被认识到的促进疾病进展的机制。本申请的目的是研究有助于BPH启动和进展的新分子机制。该应用基于我们的新的初步观察，即减弱前列腺上皮细胞中的雄激素受体信号传导诱导炎症微环境。我们假设前列腺炎症微环境有助于BPH的进展。通过本申请中的三个目标，我们寻求产生人类BPH的新型小鼠模型，使用小鼠模型确定免疫细胞对前列腺上皮细胞增殖的贡献，并鉴定由能够促进上皮细胞增殖的炎症性前列腺微环境介导的新型关键信号传导。

 DESCRIPTION (provided by applicant): Benign prostatic hyperplasia is a progressive condition in the aging men characterized by the enlargement of the periurethral regions of prostate gland due to nonmalignant proliferations in both the prostate epithelial and stromal compartments. 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. Androgen targeted therapies such as finasteride are clinically employed for the treatment of BPH. However, the MTOPS study shows that even combination therapy using finasteride and doxazosin only leads to a 66% reduction of risk for clinical progression of LUTS/BPH, suggesting the existence of unrecognized mechanisms that promote disease progression. The goal of this application is to investigate novel molecular mechanisms that contribute to BPH initiation and progression. This application is based on our novel preliminary observation that attenuating the androgen receptor signaling in prostate epithelial cells induces an inflammatory microenvironment. We hypothesize that this prostatic inflammatory microenvironment contributes to progression of BPH. Through the three Aims in this application, we seek to generate novel mouse models for human BPH, use mouse models to determine the contribution of immune cells to prostate epithelial cell proliferation, and identiy novel key signaling mediated by the inflammatory prostatic microenvironment that is capable of promoting epithelial cell proliferation.