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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结-项目3