Interleukin-8 Induced Biology in Benign Prostatic Hyperplasia

描述（由申请人提供）：良性前列腺增生（BPH）的典型特征是前列腺上皮和间质增生以及进行性增大。 BPH 与慢性炎症有关，但具体机制尚不清楚。我们报道，增生性 BPH 上皮过度表达白细胞介素 8 (IL-8)，这与生腱蛋白表达模式改变的肌成纤维细胞反应性基质表型显着相关。 IL-8 是一种有效的趋化因子，可诱导骨髓源性细胞的趋化性并刺激反应性基质/伤口修复机制。我们已经建立了过表达IL-8的人类异种移植模型和表达KC（IL-8的小鼠同源物）的转基因小鼠系，并观察到由IL-8（KC）诱导的增生性上皮和反应性基质表型，其中生腱蛋白-C和原胶原I升高。我们的初步数据表明，反应性基质可能是从循环骨髓源性纤维细胞（CD14）细胞中招募的。我们的假设是，IL-8升高的功能是激活和/或募集腺性BPH病灶处的反应性基质祖细胞，并且这种增生性反应性基质进一步驱动BPH腺体和基质增生。为了解决这一假设，提出了三个具体目标： 1. 表征 IL-8(KC)/CXCR2 信号传导和生腱蛋白-C 作为下游效应物在诱导前列腺增生中的作用。 2.确定IL-8/CXCR2受体信号传导在反应性基质祖细胞募集中的作用。 3.利用药物诱导的基因表达来靶向反应性基质细胞中的IL-8(KC)/CXCR2信号传导以解偶联信号传导，从而减弱BPH中反应性基质和上皮增生的发生。该项目的目的是确定 IL-8 在募集反应性基质中作用的基本机制，并建立概念验证，即反应性基质祖细胞和随后的反应性基质可以靶向解开关键途径，从而减弱增生表型。 公共健康相关性：本研究的目的是确定白细胞介素 8 (IL-8) 如何调节良性前列腺增生的生物学特性。该项目将使用多个模型系统提供有关关键机制和途径的数据。这些机制和途径可能会发展为治疗靶点。

DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) is typified by epithelial and stromal hyperplasia and progressive enlargement of the prostate gland. BPH is associated with chronic inflammation, however specific mechanisms are unknown. We have reported that hyperplastic BPH epithelium overexpresses interleukin-8 (IL-8) and that this correlated significantly with a myofibroblast reactive stroma phenotype with altered expression patterns of tenascin. IL-8 is a potent chemokine that induces chemotaxis of marrow-derived cells and stimulates reactive stroma / wound repair mechanisms. We have generated a human xenograft model that overexpresses IL-8 and transgenic mouse lines expressing KC (a murine homolog of IL-8) and observe a hyperplastic epithelial and reactive stroma phenotype induced by IL-8(KC) with elevated tenascin-C and pro- collagen I. Our preliminary data suggests that reactive stroma may be recruited from circulating marrow- derived progenitor fibrocyte (CD14+) cells. It is our hypothesis that elevated IL-8 functions to activate and/or recruit reactive stroma progenitor cells at foci of glandular BPH and that this hyperplastic reactive stroma further drives BPH glandular and stromal hyperplasia. To address this hypothesis three Specific Aims are proposed: 1. To characterize the role of IL-8(KC) / CXCR2 signaling and tenascin-C, as a downstream effector, in the induction of prostate hyperplasia. 2. To determine the role of IL-8 / CXCR2 receptor signaling in the recruitment of reactive stroma progenitor cells. 3. To target IL-8(KC) / CXCR2 signaling in reactive stroma cells using drug-inducible gene expression to uncouple signaling and therefore attenuate the genesis of reactive stroma and epithelial hyperplasia in BPH. The purpose of this project is to determine basic mechanisms of IL-8 action in recruiting reactive stroma and establish proof-of-concept that reactive stroma progenitor cells and subsequent reactive stroma can be targeted to uncouple key pathways in order to attenuate the hyperplastic phenotype. PUBLIC HEALTH RELEVANCE: This objective of this study is to determine how interleukin-8 (IL-8) regulates the biology of benign prostatic hyperplasia. This project will provide data on key mechanisms and pathways using several model systems. These mechanisms and pathways may evolve as therapeutic targets.