Molecular Mechanisms of Initiation of Benign Prostatic Hyperplasia

 描述(申请人提供)：良性前列腺增生症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间质中的非恶性增殖导致前列腺的尿道区扩大。据估计，50%的男性在50岁前有前列腺增生症的组织学证据，到80岁时有75%的男性有组织学证据。BPH常伴有下尿路症状(LUTS)。良性前列腺增生症很少是致命的，但如果不治疗，可能会导致严重的危及生命的并发症，如急性尿潴留。雄激素靶向治疗，如非那雄胺，在临床上用于治疗BPH。然而，MTOPS的研究表明，即使使用非那雄胺和多沙唑嗪的联合治疗也只能使LUTS/BPH的临床进展风险降低66%，这表明存在未知的促进疾病进展的机制。这项应用的目的是研究有助于BPH发生和发展的新的分子机制。这一应用是基于我们新的初步观察结果，即减弱前列腺上皮细胞中的雄激素受体信号会诱导炎症微环境。我们推测，这种前列腺炎性微环境有助于BPH的进展。通过本申请的三个目标，我们寻求建立人类BPH的新的小鼠模型，利用小鼠模型来确定免疫细胞对前列腺上皮细胞增殖的贡献，并识别能够促进上皮细胞增殖的炎性前列腺微环境介导的新的关键信号。

 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.