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：
10378476
负责人：
WILLIAM A RICKE
金额：
$ 51.82万
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/10378476
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 Epithelial Cells 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 Institutes Kidney Diseases Lead Ligands Link Lower urinary tract Magnetic Resonance Imaging Malignant neoplasm of prostate Maps Mediating Mediator of activation protein Medical Methods Modeling Molecular Molecular Mechanisms of Action Monitor Mus 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 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 preclinical study public health relevance response 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.

项目摘要分配给良性前列腺增生/肥大的较低尿路症状（LUTS）的医疗保健费用（BPH）每年数十亿美元。 BPH/LUTS是一种令人衰弱的疾病，几乎影响所有老年男性。 BPH 可以是致命的疾病（肾脏疾病/尿retention屈），并且估计有更多男性死于BPH比前列腺癌死亡。 BPH/LUTS的疗法靶向平滑肌肉收缩力使用α阻滞剂或具有5α-还原酶抑制剂的增生。尽管这些疗法可以是药用，但不是所有人有效/耐用；这使数百万人需要更有效的疗法。雌激素和下游目标在BPH/LUTS的发展和发展中很重要，但没有医疗治疗针对这些途径。 BPH/LUTS目前过度治疗的BPH/LUTS的医疗保健标准患者人口，部分原因是对病因和疾病进展的不良理解。有一个显然需要定义BPH在患者群体中的代表以及确定真正的解剖学，细胞和该疾病的分子原因。这里的澄清可能会阐明发展中的真正原因该疾病的进展以及制定有效的策略和疗法。我们和其他人有以前证明了前列腺胶原蛋白沉积与前列腺刚度，LUTS和失败医学治疗支持BPH/LUTS部分是一种纤维化疾病。此外，我们提出了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学， BPH/LUTS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，发现了通过雌激素受体（ER）-α发出信号的雌激素对于小鼠的LUTD的发展是必要的。虽然，多个基质和上皮细胞表达 ER-α，我们提供的证据表明ER-α阳性基质细胞负责增加胶原蛋白沉积。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。因此我们建议识别特定于组织的ER-？前列腺纤维化/LUTD的调节。同时，我们将确定纤维化/胶原蛋白积累是独立起作用还是与前列腺增生合作。此外，我们将确定Col1a1转录中的ER分子作用机理确定是否需要经典或非经典的ER信号传导。我们还将确定是否有选择性嗯 - ？调节剂（Ser？MS）有效治疗前列腺纤维化并减轻相关的尿液功能障碍。最后，必须提高BPH治疗效率的纤维化前列腺男性分层。为了应对这一挑战，新型的胶原蛋白MRI技术将用于评估前列腺纤维化是否可以可以在临床前模型中识别。通过建立雌激素调节的细胞和分子机械纤维化与BPH/LUTS之间的联系我们将发现一种新的BPH和有效治疗的病因。