Interleukin-8 Induced Biology in Benign Prostatic Hyperplasia

描述(申请人提供)：良性前列腺增生症(BPH)以前列腺上皮和间质的增生和进行性增大为特征。BPH与慢性炎症有关，但具体机制尚不清楚。我们已经报道，增生性BPH上皮过度表达白介素8(IL-8)，这与肌成纤维细胞反应性间质表型和Tenascin表达模式的改变显著相关。IL-8是一种强大的趋化因子，可诱导骨髓来源的细胞趋化，并刺激反应性基质/创伤修复机制。我们已经建立了过表达IL-8的人异种移植模型和表达KC(一种IL-8的小鼠同源物)的转基因小鼠系，并观察到IL-8(KC)诱导的上皮和反应性基质表型，并伴有Tenascin-C和I型胶原原的升高。我们的初步数据表明，反应性基质可能来自循环中的骨髓来源的祖细胞纤维细胞(CD14+)。我们的假设是，IL-8的升高能够激活和/或招募腺性BPH病灶处的反应性间质祖细胞，这种增生的反应性间质进一步推动BPH腺体和间质的增生。针对这一假说，提出了三个具体的目标：1.研究IL-8(KC)/CXCR2信号通路和Tenascin-C作为下游效应因子在诱导前列腺增生中的作用。2.探讨IL-8/CXCR2受体信号通路在反应性基质前体细胞募集中的作用。3.靶向IL-8(KC)/CXCR2信号通路，通过药物诱导的基因表达来解偶联信号通路，从而减轻BPH中反应性间质和上皮细胞增生的发生。本项目的目的是确定IL-8在募集反应性基质中的作用的基本机制，并建立概念验证，即反应性基质前体细胞和随后的反应性基质细胞可以被靶向解偶联关键途径，以减弱增生性表型。 公共卫生相关性：这项研究的目标是确定白介素8(IL-8)如何调节良性前列腺增生症的生物学。该项目将使用几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演变为治疗靶点。

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.