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

基本信息

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
项目类别：
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

项目摘要

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/LUTS 是一种使人衰弱的疾病，几乎影响所有老年男性。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 BPH 的人数多于前列腺癌。 BPH/LUTS 的治疗以 α 受体阻滞剂的平滑肌收缩为目标。或 5α-还原酶抑制剂引起的增生虽然这些疗法可以是药物疗法，但它们不是药物疗法。对所有人有效/持久；这使得数百万男性需要更有效的雌激素和下游疗法。目标对于 BPH/LUTS 的发生和进展很重要，但尚无药物治疗方法目前针对 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。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、此处阐明疾病的细胞和分子原因可能会阐明发育的真正原因。我们和其他人已经制定了有效的策略和疗法。先前证明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 在某种程度上是一种纤维化疾病的概念。雌激素介导前列腺纤维化和相关的 LUTD。患有 BPH/LUTS 的男性前列腺纤维化的细胞和分子起源，并了解其调节最近，发现了雌激素，特别是通过雌激素受体 (ER)-α 信号传导。尽管多种基质细胞和上皮细胞表达，但它对于小鼠 LUTD 的发展是必需的。 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。提议确定前列腺纤维化/LUTD 的组织特异性调节。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，我们将通过以下方法确定 Col1a1 转录中的 ER 分子作用机制：确定经典或非经典 ER 信号传导是否必要，我们还将确定治疗是否具有选择性。 ER-? 调节剂 (SER?Ms) 可有效治疗前列腺纤维化并缓解相关尿频最后，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通过建立雌激素调节的细胞和分子机制来识别临床前模型。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。