Estrogens stimulate prostatic collagen synthesis to drive fibrosis and LUTD

雌激素刺激前列腺胶原蛋白合成，促进纤维化和 LUTD

基本信息

批准号：
10264805
负责人：
WILLIAM A RICKE
金额：
$ 25.44万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264805
关键词：
5 Alpha-Reductase Inhibitor Address Adrenergic alpha-Antagonists Affect Anatomy Benign Benign Prostatic Hypertrophy Biological Bladder CRISPR/Cas technology Caring Cell physiology Cells Clinic Clinical Clinical Treatment Collaborations Collagen Communities Contrast Media Data Databases Deposition Development Disease Disease Progression Epithelial Cells Estrogen Receptor alpha Estrogen Receptors Estrogens Etiology Event Extracellular Matrix Fibroblasts Fibrosis Foundations Functional disorder Funding Opportunities Genetic Transcription Goals Health Care Costs Healthcare Hormone Receptor Hyperplasia Image Imaging Techniques In Vitro Institutes Instruction Lead Link Lower urinary tract Magnetic Resonance Imaging Mediator of activation protein Medical Methods Modeling Molecular Molecular Mechanisms of Action Monitor Mus Obstruction Outcome Pathway interactions Physiological Pre-Clinical Model Preclinical Testing Prevention Prostate Prostatic Prostatic hypertrophy Protocols documentation Publishing Quality of life Receptor Signaling Reproducibility Research Research Project Grants Resources Signal Transduction Smooth Muscle Smooth Muscle Myocytes Specimen Stratification Stromal Cells Techniques Testing Tissues Translating Treatment Efficacy Urethra Urinary tract Urology base cell type clinical translation clinically relevant clinically significant cost effective therapy experimental study gain of function human disease in vivo lower urinary tract symptoms men mortality risk mouse model new therapeutic target novel outreach patient population patient stratification response targeted treatment therapeutic target urinary web site

项目摘要

PROJECT SUMMARY Healthcare costs for lower urinary tract symptoms (LUTS) ascribed to benign prostatic hyperplasia (BPH) are in the billions of dollars annually. 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 in the US needing more effective therapies. The standard of medical care for BPH/LUTS currently over-treats this patient population, in part due to a poor understanding of etiology and progression. 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. This may elucidate the true causes in development and progression of the disease as well as institute effective therapies. The overarching goal of the O’Brien Center for Benign Urology Research is to identify the mechanisms that result in lower urinary tract dysfunction and prostate-related LUTS. Previous studies have 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. However, this brings up a translational challenge because treatment of prostatic fibrosis cannot occur until cellular and molecular pathways have been identified. As such, the goal is to identify the anatomical, cellular, and molecular origins of prostate fibrosis in men with BPH/LUTS. Recently, estrogens, specifically signaling through estrogen receptor (ER)α, was discovered to be necessary for the development of prostatic fibrosis and LUTD in mice. Although, multiple stromal and epithelial cells express ERα, a subpopulation of ERα positive prostatic fibroblasts and/or smooth muscle cells could be responsible for increased collagen deposition. These cells are sensitive to estrogens and produce large amounts of collagen in vitro and in vivo. Aim 1 will address the ER molecular mechanism of action in the transcription of Col1a1 by determining if classical or non-classical ER signaling is necessary. Next, collagen accumulation has been linked with BPH/LUTS, but it is uncertain if collagen/fibrosis acts independently or in collaboration with prostate hyperplasia; Aim 2 will test the hypothesis that gain of collagen function promotes LUTD independent of prostate hyperplasia. Clinical translation of our findings is a goal of the center; Aim 3 will test the hypothesis that clinically relevant antifibrotics are effective in the treatment of prostatic fibrosis. Lastly, stratification of men with fibrotic prostates is imperative to increase treatment efficacy. To address this challenge, advanced and novel collagen MR imaging techniques will be used to assess whether prostatic fibrosis can be identified in preclinical models. By establishing cellular and molecular mechanistic connections between fibrosis and BPH/LUTS as well as preclinical testing and patient stratification our collaborative and synergistic research, Project 1 will lay the groundwork for impactful discoveries that elucidate an important etiology of BPH/LUTS and may ultimately translate into the clinic.

项目概要良性前列腺增生 (BPH) 引起的下尿路症状 (LUTS) 的医疗费用在每年数十亿美元的治疗 BPH/LUTS 的目标是使用 α 受体阻滞剂或使用 5α-还原酶抑制剂治疗增生虽然这些疗法可以作为药物治疗，但它们不是药物。对所有人有效/持久；这使得美国数百万男性需要更有效的治疗标准。目前针对 BPH/LUTS 的医疗护理对这一患者群体进行了过度治疗，部分原因是对 BPH/LUTS 的了解不足显然需要将 BPH 在患者群体中的表现定义为：以及确定该疾病的真正的解剖学、细胞和分子原因，这可能会阐明真正的原因。疾病发生和进展的原因以及制定有效的治疗方法。奥布莱恩良性泌尿学研究中心的目标是确定导致尿频降低的机制先前的研究已证明前列腺胶原沉积。与前列腺僵硬、LUTS 和失败的医疗治疗相一致，支持 BPH/LUTS 的概念，部分是一种纤维化疾病，然而，这带来了前列腺纤维化治疗的转化挑战。在确定细胞和分子途径之前，这种情况不会发生。因此，我们的目标是确定患有 BPH/LUTS 的男性前列腺纤维化的解剖学、细胞和分子起源最近，雌激素，通过雌激素受体 (ER)α 进行特异性信号传导，被发现对于小鼠前列腺纤维化和 LUTD 虽然，多种基质细胞和上皮细胞表达 ERα，一个亚群。 ERα 阳性前列腺成纤维细胞和/或平滑肌细胞可能导致胶原蛋白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。目标 1 将通过确定是否经典的方法来解决 Col1a1 转录中的 ER 分子作用机制。其次，胶原蛋白的积累与 BPH/LUTS 有关，但它也与非经典 ER 信号传导有关。不确定胶原/纤维化是否独立作用或与前列腺增生共同作用；目标 2 将进行测试；胶原蛋白功能的增强促进 LUTD 的假设与前列腺增生无关。该中心的目标是转化我们的研究结果；目标 3 将检验临床相关抗纤维治疗的假设最后，对患有纤维化前列腺的男性进行分层是必要的。为了提高治疗效果，需要先进和新颖的胶原磁共振成像技术。将用于评估是否可以通过建立细胞模型来识别前列腺纤维化。纤维化和 BPH/LUTS 之间的分子机械联系以及临床前测试和患者对我们的协作和协同研究进行分层，项目 1 将为有影响力的发现奠定基础阐明了 BPH/LUTS 的重要病因学，并可能最终转化为临床。