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: 10700924
• 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/10700924
• 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; Instruction; Lead; Link; Lower urinary tract; Magnetic Resonance Imaging; Mediator; Medical; Medicine; 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; antifibrotic treatment; cell type; clinical translation; clinically relevant; clinically significant; cost; effective therapy; efficacy evaluation; 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; permissiveness; response; spectrograph; 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.

项目总结 被归因于良性前列腺增生症(BPH)的下尿路症状(LUT)的医疗费用 每年数十亿美元。α受体阻滞剂或联合用药治疗良性前列腺增生症/下尿路狭窄 用5种α还原酶抑制剂治疗增生症。虽然这些疗法可以是药物疗法，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疗法。《标准》 目前，对BPH/LUTS的医疗护理过度治疗了这一患者群体，部分原因是对 病因和进展。显然有必要将良性前列腺增生症在患者群体中的代表定义为 以及确定疾病的真正解剖、细胞和分子原因。这可能会澄清真实的 研究疾病发展和进展的原因，以及制定有效的治疗方法。最重要的是 O‘Brien良性泌尿系统研究中心的目标是确定导致低尿的机制 与前列腺相关的下尿路功能障碍。此前的研究表明，前列腺胶原蛋白沉积 与前列腺僵硬、LUTS和失败的治疗相一致，支持BPH/LUTS的概念， 在某种程度上，这是一种纤维性疾病。然而，这带来了一个翻译挑战，因为前列腺纤维化的治疗 在确定细胞和分子途径之前不可能发生这种情况。因此，我们的目标是确定 男性BPH/LUTS患者前列腺纤维化的解剖学、细胞学和分子起源。最近，雌激素， 特别是通过雌激素受体(ER)α的信号转导，被发现在卵巢癌的发生发展中是必要的。 小鼠前列腺纤维化与LUTD的关系。虽然，多个间质和上皮细胞表达ERα，这是一个亚群 ERα阳性的前列腺成纤维细胞和/或平滑肌细胞可能与胶原蛋白的增加有关 证词。这些细胞对雌激素敏感，在体外和体内都能产生大量的胶原蛋白。 目标1将通过确定是否经典的内质网分子在Col1a1转录中的作用机制 或者非经典的ER信令是必要的。其次，胶原蛋白的积累与BPH/LUTS有关，但它 不确定胶原/纤维化是单独起作用还是与前列腺增生症协同作用；Aim 2将测试 胶原蛋白功能增强促进LUTD独立于前列腺增生的假说。临床 翻译我们的发现是该中心的一个目标；目标3将测试临床上相关的抗纤维化药物的假设 在治疗前列腺纤维化方面是有效的。最后，对患有前列腺纤维化的男性进行分层治疗是当务之急。 以提高治疗效果。为了应对这一挑战，先进和新颖的胶原蛋白磁共振成像技术 将用于评估是否可以在临床前模型中识别前列腺纤维化。通过建立蜂窝网络 纤维化与BPH/LUTS以及临床前试验和患者之间的分子机制联系 将我们的协作和协同研究分层，项目1将为有影响力的发现奠定基础 这阐明了BPH/LUTS的一个重要病因，并最终可能转化为临床。