Persistence of an IL-4/IL-13 autocrine loop promotes fibrosis-mediated urinary voiding dysfunction

IL-4/IL-13 自分泌环的持续存在促进纤维化介导的尿排尿功能障碍

• 批准号: 10700930
• 负责人: Jill A. Macoska
• 金额: $ 12.69万
• 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/10700930
• 关键词: 5 Alpha-Reductase Inhibitor; Adrenergic Antagonists; Adverse effects; Aging; Apoptosis; Benign; Bladder Calculi; Bladder Dysfunction; Cell secretion; Cells; Chronic; Collagen; Data; Deposition; Development; Disease; Disease Progression; Extracellular Matrix; Feedback; Fibroblasts; Fibrosis; Functional disorder; Funding Opportunities; Genetic Transcription; Goals; Heterogeneity; Human; Impairment; In Vitro; Inflammation; Inflammatory; Instruction; Interleukin 4 Receptor; Interleukin Activation; Interleukin-13; Interleukin-4; Interleukins; Kidney; Laboratories; Left; Lower urinary tract; Macrophage; Maintenance; Mediating; Mediator; Medical; Metabolic syndrome; Molecular; Myofibroblast; Nocturia; Non-Malignant; Operative Surgical Procedures; Pathologic; Population; Prostate; Prostate Ablation; Prostatic; Prostatic Urethra; Proteins; Recurrence; Regimen; Repression; Research; Research Project Grants; STAT6 gene; Signal Transduction; Stream; Stromal Cells; Symptoms; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Urethra; Urinary Retention; Urinary tract; Urinary tract infection; Urination; Urology; Work; alpha-adrenergic receptor; autocrine; chemokine; cost; disorder risk; flexibility; improved; in vivo; inhibitor; interest; lower urinary tract symptoms; men; neutrophil; preclinical study; prostate enlargement; receptor; response; therapeutic target; transcription factor; urinary

PROJECT SUMMARY - PROJECT 3 Lower urinary tract symptoms (LUTS) are a costly and potentially critical medical problem for millions of aging men. This spectrum disorder encompasses symptoms such as weak stream, nocturia, incomplete emptying and intermittent urination, all of which are indicative of lower urinary tract dysfunction (LUTD). Surgical ablation of prostate tissue and medical approaches may improve urinary flow, but such treatments are not effective for all men, can produce adverse effects that result in discontinuation of the therapeutic regimen, and do not abrogate the risk for disease progression. If left untreated or treated ineffectively, LUTD can progress to bladder dysfunction, which can lead to urinary retention, recurrent UTI, bladder calculi, and, eventually, renal impairment. Work accomplished by the Macoska laboratory and this Center have shown that collagen accumulation around the prostatic urethra consistent with tissue fibrosis is an untreated pathobiology contributing to LUTD. The overarching goal of the O’Brien Center for Benign Urology Research is to identify mechanisms that result in lower urinary tract dysfunction and prostate-related lower urinary tract symptoms (LUTS). New evidence (presented in this application) indicates heterogeneity among peri-urethral collagen-producing cells as well as inflammatory cells within the prostatic microenvironment. Inflammatory cells secrete a medley of pro-fibrotic proteins into the prostatic microenvironment. Among these proteins, IL-4 and IL-13 are of particular interest because they share a common signaling axis which, as shown here for the first time, establishes and perpetuates an autocrine loop that activates JAK/STAT signaling to promote the expression and maintenance of IL-4, IL-13, their cognate receptors, regulatory transcription factors, and ECM components, even in the absence of inflammatory cells. Based on preliminary data presented here we hypothesize that some peri-urethral stromal cell populations establish an IL-4/IL-13 axis that self-perpetuates, induces myofibroblast phenoconversion and survival, and upregulates collagen accumulation, thereby promoting consequent urinary voiding dysfunction. To test this hypothesis, Project 3 will: 1) Determine whether signaling through the IL-4 receptor creates a STAT6- and GATA-3-mediated positive feedback loop; 2) Elucidate the mechanisms through which the IL-4/IL-13 axis promotes myofibroblast phenoconversion and concordant collagen expression; 3) Determine whether IL-4 pathologically represses myofibroblast apoptosis and thereby promotes myofibroblast survival, and 4) Test whether the IL-4/IL-13 signaling axis promotes lower urinary tract fibrosis and urinary voiding dysfunction in vivo. The results of these preclinical studies will elucidate previously unknown interleukin-mediated molecular and cellular mechanisms that promote lower urinary tract fibrosis and dysfunction. Using JAK/STAT inhibitors to therapeutically target this potentially self-perpetuating mechanism may ‘break the cycle’ and successfully treat recalcitrant peri-urethral prostatic fibrosis contributing to LUTD development and progression.

项目摘要 - 项目 3 对于数以百万计的老年人来说，下尿路症状（LUTS）是一个代价高昂且潜在严重的医疗问题 这种谱系会导致尿流无力、夜尿、排空不完全等症状。 间歇性排尿，所有这些都表明下尿路功能障碍（LUTD）。 前列腺组织和医疗方法可能会改善尿流量，但此类治疗并非对所有人都有效 男性，可能会产生导致治疗方案停止的不良反应，并且不会废除 如果不治疗或治疗无效，LUTD 可能会进展至膀胱。 功能障碍，可能导致尿潴留、复发性尿路感染、膀胱结石，并最终导致肾功能损害。 Macoska 实验室和该中心完成的工作表明，胶原蛋白在周围积聚 与组织纤维化一致的前列腺尿道是导致 LUTD 的未经治疗的病理生物学。 奥布莱恩良性泌尿学研究中心的总体目标是确定导致 下尿路功能障碍和前列腺相关的下尿路症状（LUTS）。 （本申请中提出）表明尿道周围胶原蛋白生成细胞之间的异质性以及 炎症细胞分泌多种促纤维化物质 在这些蛋白质中，IL-4 和 IL-13 特别令人感兴趣。 因为它们共享一个共同的信号轴，正如这里首次所示，该信号轴建立并延续 激活 JAK/STAT 信号传导的自分泌环路，以促进 IL-4、IL-13 的表达和维持， 它们的同源受体、调节转录因子和 ECM 成分，即使没有 根据这里提供的初步数据，我们认为一些尿道周围基质。 细胞群建立自我延续的 IL-4/IL-13 轴，诱导肌成纤维细胞表型转化并 存活，并上调胶原蛋白积累，从而促进随后的排尿功能障碍。 为了检验这一假设，项目 3 将：1) 确定通过 IL-4 受体的信号传导是否会产生 STAT6- 和 GATA-3 介导的正反馈环；2) 阐明 IL-4/IL-13 轴的机制； 促进肌成纤维细胞表型转化和一致的胶原蛋白表达 3) 确定 IL-4 是否存在； 病理上抑制肌成纤维细胞凋亡，从而促进肌成纤维细胞存活，4) 测试 IL-4/IL-13信号轴是否促进体内下尿路纤维化和排尿功能障碍。 这些临床前研究的结果将阐明以前未知的白细胞介素介导的分子和 使用 JAK/STAT 抑制剂促进下尿路纤维化和功能障碍的细胞机制。 治疗上针对这种潜在的自我延续机制可能会“打破循环”并成功治疗 顽固性尿道周围前列腺纤维化导致 LUTD 的发生和进展。