Perturbation of the hormonal milieu produces lower urinary tract dysfunction

荷尔蒙环境的扰动会导致下尿路功能障碍

• 批准号: 9142065
• 负责人: WILLIAM A RICKE
• 金额: $ 21.47万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9142065
• 关键词: Address; Adrenergic alpha-Antagonists; Adverse effects; Affect; Age; Aging-Related Process; Androgens; Benign Prostatic Hypertrophy; Binding; Bladder; Bladder neck obstruction; Cells; Clinical; Clinical Treatment; Collagen; Collagen Fibril; Data; Deposition; Development; Dimerization; Disease; Disease Progression; Estradiol; Estrogen Receptors; Estrogens; Etiology; Event; Extracellular Matrix; Fibrosis; Functional disorder; Generations; Genetic Transcription; Genetic study; Genitourinary system; Goals; Growth; Healthcare; Homodimerization; Hormonal; Hormone use; Hormones; Image; Laboratories; Lead; Ligands; Link; Lower urinary tract; Mediating; Mediator of activation protein; Medical; Methods; Microscopy; Molecular; Monitor; Morbidity - disease rate; Mus; Nervous System Physiology; Neuraxis; Obstruction; Operative Surgical Procedures; Oxidoreductase; Pathology; Pathway interactions; Patients; Physiological; Prevention; Process; Prostate; Prostatic hypertrophy; Publishing; Quality of life; Receptor Signaling; Research; Risk; Selective Estrogen Receptor Modulators; Smooth Muscle; Technology; Testing; Testosterone; Tissue Recombination; Tissues; Transgenic Mice; Urethra; androgenic; animal imaging; clinically relevant; cost; expectation; experience; histological image; imaging platform; improved; in vivo; inhibitor/antagonist; loss of function; lower urinary tract symptoms; men; mortality; novel; prevent; prostate transurethral resection; receptor; reconstruction; second harmonic; standard of care; targeted treatment; therapeutic target; urinary; urinary bladder neck; urologic

Clinical treatment for lower urinary tract symptoms (LUTS) ascribed to benign prostatic hypertrophy (BPH) in men is a significant cost to healthcare (>$4-billion/year), adversely affecting quality of life, and contribute to the mortality risk in men. The long term objectives of this project are to better understand the molecular and anatomical processes involved in manifestation of LUTS and to develop better methods for prevention and treatment of LUTS. Lower urinary tract dysfunction (LUTD), including bladder outlet obstruction (BOO), may occur through a number of physical obstructive events leading to physiological alteration of bladder function. Although bladder obstruction has typically been associated with nodular prostatic growth, the actual cause(s) of LUTS in men with clinical BPH remain unknown and may encompass several additional physiological/anatomical pathologies including bladder neck stricture, altered central nervous system function, and more recently prostatic fibrosis. Recent published and preliminary studies demonstrate that the tissue microenvironment of the prostate is permissive for ECM deposition and fibrosis. Such fibrosis may increase prostate stiffness and promote urethral rigidity to produce an obstruction and hence lead to LUTS. The development and progression of LUTS has been clearly linked with fibrosis, yet it is not currently monitored or therapeutically targeted in men writhe with LUTD. Rather, medical approaches targeting smooth muscle contractility (e.g. alpha blockers), androgenic pathways [5-�-reductase inhibitors (5aRI)], or surgical methods [e.g. transurethral resection of the prostate (TURP)] are used to manage LUTS. Although these approaches may improve urinary flow a number of problems exist with this standard of care including: treatments are not effective in all men, elicit side-effects, and do not abolish the risk of disease progression. While the etiology of BPH remains largely unclear available data are consistent with the hypothesis that changing hormone levels, especially estradiol-17� (E2) and testosterone (T), are underlying causes of BPH/LUTS. Use of 5aRIs support this concept, because these therapies target the androgenic pathway. However, paradoxically androgen levels decrease as men age while E2 and E2:T ratios significantly increase. This posits that estrogens may be an important pathway in the etiology or persistence of BPH and associated LUTS. Estrogens primarily mediate their effects by binding two receptors; estrogen receptor (ER)-� and ER-�. ER transcription is further regulated by the capacity of the liganded receptor to homodimerize (ER-�/� or ER-�/�) or heterodimerize (ER-�/�). New unpublished data from our laboratory and others implicate E2 as a key mediator of LUTD. Our preliminary data implicate E2/ER-signaling via ER-�/� homodimerization as the key molecular mediator of LUTD. We hypothesize that abnormalities within the lower urogenital tract are mediated by inappropriate E2/ER-signaling that leads to urethral fibrosis and decreased urinary function. We further hypothesize that therapeutically targeting ERs will prevent the development of prostatic fibrosis and hence LUTD.

男性良性前列腺肥大 (BPH) 引起的下尿路症状 (LUTS) 的临床治疗是一项巨大的医疗费用（>40 亿美元/年），对生活质量产生不利影响，并增加男性的死亡风险。该项目的长期目标是更好地了解 LUTS 表现所涉及的分子和解剖学过程，并开发更好的方法来预防和治疗下尿路功能障碍。 (LUTD)，包括膀胱出口梗阻 (BOO)，可能是通过导致膀胱功能生理改变的许多身体梗阻事件而发生的，尽管膀胱梗阻通常与结节性前列腺生长有关，但 LUTS 的实际原因是。患有临床 BPH 的男性仍然未知，可能还包括几种其他的生理/解剖学病理，包括膀胱颈狭窄、中枢神经系统功能改变以及最近发表的前列腺纤维化，最近发表的初步研究表明前列腺的组织微环境是允许的。这种纤维化可能会增加前列腺硬度并促进尿道僵硬，从而导致 LUTS。LUTS 的发生和进展与纤维化明显相关，但目前尚未对男性进行监测或治疗。相反，针对平滑肌收缩力的医疗方法（例如 α 受体阻滞剂）、雄激素途径 [5-β-还原酶抑制剂 (5aRI)] 或手术方法。 [例如经尿道前列腺切除术 (TURP)] 用于治疗 LUTS，尽管这些方法可以改善尿流量，但这种护理标准存在许多问题，包括：治疗并非对所有男性有效，会引起副作用，以及虽然 BPH 的病因在很大程度上仍不清楚，但现有数据与激素水平变化（尤其是雌二醇-17� (E2) 和睾酮 (T)）是根本原因的假设是一致的。 BPH/LUTS 的使用支持了这一概念，因为这些疗法以雄激素途径为目标，然而，矛盾的是，随着男性年龄的增长，雄激素水平下降，而 E2 和 E2:T 比率显着增加，这表明雌激素可能是其中的一个重要途径。 BPH 和相关 LUTS 的病因或持续性主要通过结合雌激素受体 (ER)-� 来介导其作用，并且 ER-� 的转录能力进一步受到调节。我们的实验室和其他实验室未发表的新数据表明 E2 是 LUTD 的关键介质。通过 ER-β/β 同二聚化的 E2/ER 信号作为 LUTD 的关键分子介质，我们认为下泌尿生殖道内的异常是由不适当的介导的。 E2/ER 信号传导导致尿道纤维化和泌尿功能下降，我们进一步开发了针对 ER 的治疗将阻止前列腺纤维化的发展，从而预防 LUTD。