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

项目摘要--项目3 下尿路症状(LUT)是数百万人面临的一个昂贵且潜在的严重医疗问题 男人。这种谱系障碍包括弱血流、夜尿、排空不全和 间歇性排尿，所有这些都表明下尿路功能障碍(LUTD)。外科消融术 前列腺组织和医学方法可能会改善尿流，但这些治疗并不是对所有人都有效 男性，会产生不良影响，导致停止治疗方案，并且不会被废除 疾病进展的风险。如果不治疗或治疗无效，LUTD可能会进展到膀胱 功能障碍，可导致尿潴留、反复尿路感染、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研究表明，周围的胶原蛋白积累 前列腺尿道与组织纤维化相一致，是导致LUTD的未经治疗的病理生物学因素。这个 奥布莱恩良性泌尿学研究中心的首要目标是确定导致 下尿路功能障碍和前列腺相关下尿路症状(LUTS)。新证据 (在本申请中呈现)表明尿道部周围的胶原生成细胞以及 前列腺微环境中的炎性细胞。炎症细胞分泌一系列促纤维化因子 蛋白质进入前列腺微环境。在这些蛋白质中，IL-4和IL-13尤其令人感兴趣 因为它们共享一个共同的信号轴，如这里第一次显示的那样，它建立并永久存在 一个自分泌环路，激活JAK/STAT信号，促进IL-4、IL-13、 它们的同源受体、调节转录因子和细胞外基质成分，即使在没有 炎性细胞。根据这里提供的初步数据，我们假设某些尿路周围间质 细胞群建立IL-4/IL-13轴，自我永存，诱导肌成纤维细胞表型转换和 存活，并上调胶原蛋白的积累，从而促进随之而来的排尿功能障碍。至 验证这一假设，项目3将：1)确定通过IL-4受体的信号是否产生STAT6- 和GATA-3介导的正反馈环；2)阐明IL-4/IL-13轴的作用机制 促进肌成纤维细胞表型转化和协调的胶原表达；3)确定IL-4 病理上抑制肌成纤维细胞的凋亡，从而促进肌成纤维细胞的存活，以及4)测试 IL-4/IL-13信号轴在体内是否促进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导性分子和 促进下尿路纤维化和功能障碍的细胞机制。使用JAK/STAT抑制剂 从治疗的角度来看，这种潜在的自我维持机制可能会“打破循环”，并成功治疗 顽固性前列腺周围纤维化导致LUTD的发生和发展。

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.