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

项目总结 下尿路症状(LUT)的医疗费用归因于良性前列腺增生/肥大 (BPH)是每年数十亿美元。BPH/LUTS是一种使人衰弱的疾病，几乎影响所有老年男性。前列腺增生症 可能是一种致命的疾病(肾脏疾病/尿潴留)，据估计，在世界范围内，更多的男性 死于良性前列腺增生症而不是前列腺癌。α受体阻滞剂治疗良性前列腺增生症/下尿路综合征的靶向平滑肌收缩功能 或用5种α-还原酶抑制剂治疗增生症。虽然这些疗法可以是药物疗法，但它们不是 对所有人都有效/持久；这使得数百万男性需要更有效的治疗。雌激素及其下游 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 指向这些小路。BPH/LUTS的医疗标准目前过度治疗BPH/LUTS 患者群体，部分原因是对疾病的病因和进展缺乏了解。有一个 显然需要定义前列腺增生症在患者群体中的代表以及确定真正的解剖学， 这种疾病的细胞和分子原因。这里的澄清可能会阐明发展的真正原因 以及制定有效的战略和治疗方法。我们和其他人有 先前证实的前列腺胶原沉积与前列腺僵硬、LUTS一致，但失败了 医学治疗支持BPH/LUTS在一定程度上是一种纤维化疾病的概念。此外，我们建议 雌激素介导了前列腺纤维化和相关的LUTD。这项研究的目标是识别解剖学上的， 男性BPH/LUTS患者前列腺纤维化的细胞和分子起源，并了解其调节机制 雌激素途径。最近，雌激素被发现，特别是通过雌激素受体(ER)-α传递信号。 在小鼠LUTD的发生发展中是必要的。尽管如此，多个间质和上皮细胞表达 ER-α，我们提供了ER-α阳性间质细胞导致胶原沉积增加的证据。 这些细胞对雌激素敏感，在体外和体内都能产生大量的胶原蛋白。因此我们 建议鉴定组织特异性ER-？前列腺纤维化的调节/LUTD。同时我们也会 确定纤维化/胶原堆积是独立起作用还是与前列腺增生症协同起作用。 此外，我们将通过以下方式确定内质网分子在Col1a1转录中的作用机制 确定是否需要经典或非经典ER信令。我们还将确定是否有选择性治疗 呃-？调节剂(SER？MS)在治疗前列腺纤维化和缓解相关尿液方面有效 功能障碍。最后，对患有前列腺纤维化的男性进行分层治疗对于提高BPH的治疗效果是必不可少的。 为了应对这一挑战，将使用新的胶原蛋白MRI技术来评估前列腺纤维化是否可以 在临床前模型中被识别。通过建立雌激素调节的细胞和分子机制 纤维化与BPH/LUTS的关系我们将发现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.