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

前列腺纤维化和下尿路功能障碍发展中的雌激素途径

• 批准号: 10597683
• 负责人: WILLIAM A RICKE
• 金额: $ 51.53万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597683
• 关键词: 5 Alpha-Reductase Inhibitor; Address; Adrenergic alpha-Antagonists; Affect; Aging; Anatomy; Benign Prostatic Hypertrophy; Binding; Biological; Bladder; CRISPR/Cas technology; Caring; Cells; Clinical; Clinical Treatment; Collaborations; Collagen; Communities; Data; Deposition; Development; Disease; Disease Progression; Epithelial Cells; Epithelium; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Etiology; Event; Extracellular Matrix; Fibrosis; Functional disorder; Future; Genes; Genetic Transcription; Goals; Health Care Costs; Healthcare; Hormone Receptor; Hormones; Human; Hyperplasia; Hypertrophy; Image; In Vitro; Kidney Diseases; Lead; Ligand Binding; Link; Lower urinary tract; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Maps; Mediating; Mediator; Medical; Medicine; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Mus; Non-Invasive Detection; Obstruction; Outcome; Pathway interactions; Patient Monitoring; Patients; Physiological; Pre-Clinical Model; Prevention; Process; Prostate; Prostatic; Prostatic hypertrophy; Protocols documentation; Publishing; Quality of life; Receptor Signaling; Regulation; Reproducibility; Research; Resources; Response Elements; Selective Estrogen Receptor Modulators; Signal Transduction; Smooth Muscle; Specimen; Stratification; Stromal Cells; Techniques; Testing; Therapeutic; Time; Tissues; Transcription Factor AP-1; Treatment Efficacy; Urethra; Urinary Retention; aged; cell type; clinically relevant; cost; effective therapy; efficacy evaluation; experience; experimental study; imaging modality; imaging probe; improved; in vivo; innovation; lower urinary tract symptoms; men; mortality risk; mouse model; new therapeutic target; novel; outreach; patient population; patient stratification; permissiveness; preclinical study; public health relevance; response; spectrograph; targeted treatment; therapeutic target; transcription factor; ultrasound; urinary; urologic

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.

项目概要 良性前列腺增生/肥大引起的下尿路症状 (LUTS) 的医疗费用 （BPH）每年达数十亿美元。 BPH/LUTS 是一种使人衰弱的疾病，几乎影响所有老年男性。前列腺肥大 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 死于前列腺增生症的人数多于前列腺癌。使用 α 阻滞剂治疗 BPH/LUTS 的目标是平滑肌收缩力 或5α-还原酶抑制剂引起的增生。尽管这些疗法可以作为药物治疗，但它们并不 对所有人有效/持久；这使得数百万男性需要更有效的治疗。雌激素及其下游 目标对于 BPH/LUTS 的发生和进展很重要，但尚无药物治疗方法 针对这些途径。目前 BPH/LUTS 的医疗护理标准对 BPH/LUTS 进行了过度治疗 患者群体，部分原因是对疾病的病因和进展了解甚少。有一个 显然需要定义 BPH 在患者群体中代表什么以及确定真正的解剖学、 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 和这种疾病的进展以及制定有效的策略和疗法。我们和其他人有 先前证明前列腺胶原沉积与前列腺僵硬、LUTS 一致，但失败了 支持 BPH/LUTS 部分是一种纤维化疾病这一概念的医学治疗。此外我们建议 雌激素介导前列腺纤维化和相关的 LUTD。这项研究的目标是确定解剖学、 患有 BPH/LUTS 的男性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。最近，发现了雌激素，特别是通过雌激素受体 (ER)-α 发出信号 对于小鼠 LUTD 的发展是必需的。尽管多种基质细胞和上皮细胞表达 ER-α，我们提供的证据表明 ER-α 阳性基质细胞导致胶原蛋白沉积增加。 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 建议鉴定组织特异性 ER-？前列腺纤维化/LUTD 的调节。同时我们将 确定纤维化/胶原蛋白积累是否独立作用或与前列腺增生共同作用。 此外，我们将通过以下方式确定 Col1a1 转录中的 ER 分子作用机制： 确定是否需要经典或非经典 ER 信号传导。我们还将确定治疗是否有选择性 ER-？调节剂 (SER?Ms) 可有效治疗前列腺纤维化并缓解相关的尿频 功能障碍。最后，对患有纤维化前列腺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，新型胶原 MRI 技术将用于评估前列腺纤维化是否可以 在临床前模型中被识别。通过建立雌激素调节的细胞和分子机制 通过了解纤维化与 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。