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: 10022319
• 负责人: Jill A. Macoska
• 金额: $ 9.03万
• 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/10022319
• 关键词: 5 Alpha-Reductase Inhibitor; Adrenergic Antagonists; Adverse effects; Aging; Apoptosis; Benign; Bladder Calculi; Bladder Dysfunction; Cells; Chronic; Collagen; Data; Deposition; Development; Disease; Disease Progression; Extracellular Matrix; Feedback; Fibroblasts; Fibrosis; Functional disorder; Funding Opportunities; Genetic Transcription; Goals; Heterogeneity; Human; IL4R gene; Impairment; In Vitro; Inflammation; Inflammatory; Instruction; Interferons; Interleukin 4 Receptor; Interleukin Activation; Interleukin-13; Interleukin-4; Interleukins; Kidney; Laboratories; Lead; Left; Lower urinary tract; Maintenance; Mediating; Mediator of activation protein; Medical; Metabolic syndrome; Molecular; Myofibroblast; Nocturia; Non-Malignant; Operative Surgical Procedures; Pathologic; Population; Prostate; Prostate Ablation; Prostatic; Prostatic Urethra; Proteins; Recurrence; Regimen; Research; Research Project Grants; STAT6 gene; Signal Transduction; Stream; Stromal Cells; Symptoms; T-Lymphocyte; TNF gene; Testing; Therapeutic; Time; Tissues; Urethra; Urinary Retention; Urinary tract; Urinary tract infection; Urination; Urology; Work; alpha-adrenergic receptor; autocrine; base; chemokine; cost; disorder risk; flexibility; improved; in vivo; inhibitor/antagonist; interest; interleukin-13 receptor; lower urinary tract symptoms; macrophage; 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 较低的尿路症状（LUTS）是数百万老龄化的昂贵且潜在的关键医疗问题 男人。这种频谱障碍涵盖了符号，例如弱流，夜尿，不完整的排空和 间歇性排尿，所有这些都表明尿路功能障碍（LUTD）。手术消融 前列腺组织和医疗方法可能会改善尿流量，但这种治疗对所有人都不有效 男性会产生不良反应，导致治疗方案中断，并且不会废除 疾病进展的风险。如果未治疗或无效治疗，Lutd可以发展为膀胱 功能障碍，可能导致尿位率，复发性UTI，膀胱结石以及最终导致肾功能障碍。 Macoska实验室和该中心完成的工作表明，胶原蛋白的积累 与组织纤维化一致的前列腺尿道是一种未经治疗的病理生物学，导致LUTD。 奥布莱恩良性泌尿外科研究中心的总体目标是确定导致的机制 较低的尿路功能障碍和前列腺相关的下尿路符号（LUTS）。新证据 （在此应用中提出）表明尿道周围胶原蛋白的细胞之间的异质性以及 前列腺微环境中的炎症细胞。炎症细胞秘密促纤维化混合体 蛋白质进入前列腺微环境。在这些蛋白质中，IL-4和IL-13特别有趣 因为它们共享一个通用的信号轴，如下所示，它首次建立和永久 激活JAK/STAT信号的自分泌环以促进IL-4，IL-13的表达和维护 它们的同源受体，调节转录因子和ECM成分，即使没有 炎性细胞。根据此处提供的初步数据，我们假设某些尿道周围基质 细胞种群建立一个自我延长，诱导肌纤维细胞表现和的IL-4/IL-13轴 生存，并上调胶原蛋白的积累，从而促进随后的尿液功能障碍。到 检验该假设，项目3将：1）确定通过IL-4受体信号传导是否会产生STAT6- 和GATA-3介导的阳性反馈回路； 2）阐明IL-4/IL-13轴的机制 促进成肌纤维细胞表现和一致的胶原蛋白表达； 3）确定IL-4是否 病理上反映肌纤维细胞凋亡，从而促进肌纤维细胞存活，4）测试 IL-4/IL-13信号轴是否促进体内较低的尿路纤维化和尿液功能障碍。 这些临床前研究的结果将阐明以前未知的白介素介导的分子和 促进较低尿路纤维化和功能障碍的细胞机制。使用jak/stat抑制剂 从治疗上瞄准这种潜在的自我延续机制可能会“打破周期”并成功治疗 尿道周围前列腺纤维化有助于LUTD发育和进展。