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

• 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
• 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

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.

项目摘要 良性前列腺增生（BPH）引起的下尿路症状（LUTS）的医疗保健费用在 每年数十亿美元。BPH/LUTS的治疗以α受体阻滞剂或 5α-还原酶抑制剂。虽然这些疗法可以是药用的，但它们不是 对所有人都有效/持久;这使得美国数百万男性需要更有效的治疗。的标准 目前对BPH/LUTS的医疗护理过度治疗了这一患者人群，部分原因是对 病因和进展。显然需要将BPH在患者人群中的代表定义为 以及确定疾病的真正解剖学、细胞和分子原因。这也许能说明 疾病的发展和进展的原因，并制定有效的治疗方法。总体 奥布莱恩良性泌尿学研究中心的目标是确定导致下尿路疾病的机制。 尿道功能障碍和前列腺相关的LUTS。先前的研究表明前列腺胶原沉积 与前列腺僵硬、LUTS和支持BPH/LUTS概念的失败医学治疗一致， 一种纤维化疾病然而，这带来了一个转化的挑战，因为前列腺纤维化的治疗 在细胞和分子途径被确定之前不会发生。因此，目标是确定 BPH/LUTS患者前列腺纤维化的解剖学、细胞和分子起源。最近，雌激素， 特别是通过雌激素受体（ER）α的信号传导，被发现是发展所必需的。 前列腺纤维化和LUTD。虽然，多种基质和上皮细胞表达ERα， ERα阳性的前列腺成纤维细胞和/或平滑肌细胞可能与胶原增加有关 证词这些细胞对雌激素敏感，并在体外和体内产生大量的胶原蛋白。 目的1将通过确定是否经典的ER基因在Col 1a 1的转录中起作用来阐明ER分子机制。 或非经典ER信号传导是必需的。其次，胶原蛋白的积累与BPH/LUTS有关，但它 不确定胶原蛋白/纤维化是独立作用还是与前列腺增生协同作用; Aim 2将测试 胶原蛋白功能的获得促进LUTD独立于前列腺增生的假设。临床 我们的研究结果的翻译是中心的目标;目标3将测试假设，临床相关的抗纤维化药物 有效治疗前列腺纤维化。最后，对患有前列腺纤维化的男性进行分层是必要的 以提高治疗效果。为了应对这一挑战，先进的新型胶原蛋白MR成像技术 将用于评估是否可以在临床前模型中识别前列腺纤维化。通过建立细胞 纤维化和BPH/LUTS之间的分子机制联系以及临床前测试和患者 通过对我们的合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 这阐明了BPH/LUTS的重要病因，并可能最终转化为临床。