Estrogen pathways in the development of prostatic fibrosis and lower urinary tract dysfunction

项目摘要 良性前列腺增生/肥大导致的下尿路症状（LUTS）的医疗费用 (BPH)是每年数十亿美元。BPH/LUTS是一种几乎影响所有老年男性的衰弱性疾病。BPH 可能是一种致命的疾病（肾病/尿潴留），据估计，在世界范围内， 死于前列腺增生症的人比死于前列腺癌的人多。BPH/LUTS的治疗以α受体阻滞剂的平滑肌收缩性为目标 或5α-还原酶抑制剂引起的增生。虽然这些疗法可以是药用的，但它们不是 对所有人有效/持久;这使得数百万男性需要更有效的治疗。雌激素和下游 这些靶点在BPH/LUTS的发展和进展中很重要，但目前还没有药物治疗方法 针对这些途径。BPH/LUTS的医疗护理标准目前过度治疗BPH/LUTS 患者人群，部分原因是对疾病的病因和进展了解不足。有一个 显然需要定义BPH在患者人群中代表什么以及识别真正的解剖学， 细胞和分子的原因。这里的澄清可以阐明发展的真正原因 以及制定有效的策略和治疗方法。我们和其他人已经 先前证实的前列腺胶原沉积与前列腺僵硬、LUTS和失败 医学治疗支持BPH/LUTS部分是纤维化疾病的概念。此外，我们建议 雌激素介导前列腺纤维化和相关的LUTD。这项研究的目的是确定解剖， 前列腺纤维化的细胞和分子起源，并了解其调节 雌激素途径近年来，人们发现了雌激素，特别是通过雌激素受体（ER）-α信号传导的雌激素 是小鼠LUTD发展所必需的。虽然，多个基质和上皮细胞表达 ER-α，我们提供证据表明ER-α阳性基质细胞负责增加胶原沉积。 这些细胞对雌激素敏感，并在体外和体内产生大量胶原蛋白。因此我们 建议确定组织特异性ER-？前列腺纤维化/LUTD的调节。同时我们将 确定纤维化/胶原积聚是独立作用还是与前列腺增生协同作用。 此外，我们将通过以下方法确定ER在Col 1a 1转录中的分子作用机制 确定是否需要经典或非经典ER信号传导。我们还将确定治疗选择性 呃-？调制器（SER？MS）在治疗前列腺纤维化和减轻相关的尿 功能障碍最后，对患有前列腺纤维化的男性进行分层对于提高BPH治疗效果至关重要。 为了应对这一挑战，新的胶原MRI技术将用于评估前列腺纤维化是否可以 在临床前模型中进行鉴定。通过建立雌激素调节的细胞和分子机制， 纤维化和BPH/LUTS之间的联系，我们将发现BPH的新病因和有效的治疗方法。

PROJECT SUMMARY Healthcare costs for lower urinary tract symptoms (LUTS) ascribed to benign prostatic hyperplasia/hypertrophy (BPH) are billions of dollars annually. BPH/LUTS is a debilitating disease that affects nearly all aged men. BPH can be a lethal disease (kidney disease/urinary retention) and world-wide it has been estimated that more men die from BPH than prostate cancer. Therapies for BPH/LUTS target smooth muscle contractility with α-blockers or hyperplasia with 5α-reductase inhibitors. Although these therapies can be medicinal, they are not effective/durable for all; this leaves millions of men needing more effective therapies. Estrogens and downstream targets are important in the development and progression of BPH/LUTS, yet there are no medical treatments directed at these pathways. The standard of medical care for BPH/LUTS currently over-treats the BPH/LUTS patient population, in part due to a poor understanding of etiology and progression of the disease. There is an apparent need to define what BPH represents in patient populations as well as to identify the true anatomic, cellular, and molecular causes of the disease. Clarification here may elucidate the true causes in development and progression of this disease as well as institute effective strategies and therapies. We and others have previously demonstrated prostatic collagen deposition coincident with prostate stiffness, LUTS, and failed medical treatment supporting the concept that BPH/LUTS is, in part, a fibrotic disease. Moreover we propose estrogens mediate prostate fibrosis and associated LUTD. The goal of this research is to identify the anatomical, cellular, and molecular origins of prostate fibrosis in men with BPH/LUTS and understand its regulation by the estrogen pathway. Recently, estrogens, specifically signaling through estrogen receptor (ER)-α, was discovered to be necessary for the development of LUTD in mice. Although, multiple stromal and epithelial cells express ER-α, we provide evidence that ER-α positive stromal cells are responsible for increased collagen deposition. These cells are sensitive to estrogens and produce large amounts of collagen in vitro and in vivo. Therefore we propose to identify the tissue specific ER-? regulation of prostate fibrosis/LUTD. At the same time we will determine if fibrosis/collagen accumulation acts independently or in collaboration with prostate hyperplasia. Additionally, we will determine the ER molecular mechanism of action in the transcription of Col1a1 by determining if classical or non-classical ER signaling is necessary. We will also determine if therapeutic selective ER-? modulators (SER?Ms) are effective in the treatment of prostate fibrosis and alleviate associated urinary dysfunction. Lastly, stratification of men with fibrotic prostates is imperative to increase BPH treatment efficacy. To address this challenge, novel collagen MRI techniques will be used to assess whether prostatic fibrosis can be identified in preclinical models. By establishing estrogen regulated cellular and molecular mechanistic connections between fibrosis and BPH/LUTS we will discover a new etiology for BPH and effective treatments.