Impact of Inflammation on Adult Prostate Stem Cells

良性前列腺增生症(BPH)的定义是上皮和间质细胞在前列腺内的扩张 前列腺移行区。虽然早期BPH间质细胞有较大的扩张，但上皮细胞 前列腺增生是导致较大症状性前列腺增生症的重要因素。虽然许多研究都表明 慢性顽固性炎症在BPH发生发展中的作用及其机制 对细胞增殖和增殖的影响尚不清楚。众所周知，炎症会产生微环境。 富含细胞因子、生长因子和其他促进前列腺上皮细胞增殖的形态因子， 包括基础前列腺干细胞(BPSC)。控制和限制炎症的调控机制- 在正常的动态平衡条件下诱导的上皮细胞增殖还没有很好的定义，代表着一种 在理解炎症、失控的细胞生长和疾病之间的潜在联系方面存在重大缺陷 前列腺肥大。本文报告的数据确定了控制前列腺上皮细胞扩张和 为更好地定义炎症诱导的前列腺调节的拟议研究奠定了基础 导致增殖的上皮细胞的增殖。了解参与炎症的途径- 诱导的细胞扩增将为开发新的阻断方法提供基础 不受控制的上皮生长。 成体基本前列腺干细胞(BPSC)是维持和修复细胞完整性的特化细胞。 然而，描述炎症对成人bPSC影响的研究有限。以前的数据 来自我们实验室的研究表明，炎症刺激bPSC的扩张，并产生基底和管腔 与非炎症(幼稚)的bPSC相比，体内的上皮细胞增生以及更大的有机物， 对这些细胞显示出持续的增殖效应。鉴于炎症促使bPSC向腔内转移 细胞转化，这需要雄激素受体(AR)和这里报道的数据，炎症稳定 通过磷酸化和IL-1α及其自然产生的抑制剂IL-1ra的AR，其中IL-1α抑制AR的表达 IL1ra增强表达，导致bPSC驱动的上皮细胞扩张。根据这些数据，我们 假设炎症驱动AR稳定，从而驱动bPSC扩张和上皮 良性前列腺增生症。为了检验这一假设，我们建议定义炎症诱导的分子基础 AR稳定化，使用新的转基因小鼠评估通路影响并定义AR依赖 BPSC的程序性改变既与增殖有关，也与上皮增生有关。

Benign prostatic hyperplasia (BPH) is defined by the expansion of both epithelial and stromal cells within the transition zone of the prostate. Although there is greater expansion of stromal cells in early BPH, epithelial hyperplasia is a significant contributor to larger symptomatic BPH prostates. While numerous studies have linked chronic and recalcitrant inflammation to the development of BPH, the mechanisms by which inflammation leads to cellular proliferation and hyperplasia are unclear. It is known that inflammation produces a microenvironment rich in cytokines, growth factors, and other morphogens that promote proliferation of prostate epithelial cells, including basal prostate stem cells (bPSC). The regulatory mechanisms that control and limit inflammation- induced epithelial cell proliferation under normal homeostatic conditions are not well defined and represent a significant deficit in understanding the potential link between inflammation, uncontrolled cellular growth and prostate enlargement. Data reported herein identify pathways controlling prostate epithelial cell expansion and form the foundation for proposed studies to better define the regulation of inflammation-induced prostate epithelial cell proliferation that leads to hyperplasia. Understanding the pathways involved in inflammation- induced cellular expansion will provide a foundation for the development of novel approaches to block uncontrolled epithelial growth. Adult basal prostate stem cells (bPSC) are specialized cells that maintain and repair the cellular integrity of the prostate; however, studies describing the effect of inflammation on adult bPSC are limited. Previous data from our laboratories show that inflammation stimulates bPSC expansion and generates basal and luminal epithelial hyperplasia in vivo as well as larger organoids compared to non-inflamed (naïve) bPSC ex vivo, demonstrating a sustained proliferative effect on these cells. Given that inflammation drives a bPSC to luminal cell transition, which requires androgen receptor (AR) and the data reported herein that inflammation stabilizes AR via phosphorylation and IL-1α and its naturally occurring inhibitor, IL-1ra, where IL-1α inhibits AR expression and IL1ra enhances expression leading to bPSC-driven expansion of epithelial cells. Based on these data, we hypothesize that inflammation drives AR stabilization that drives bPSC expansion and epithelial hyperplasia in BPH. To test the hypothesis we propose to define the molecular basis for inflammation induced AR stabilization, evaluate pathway impact using novel genetically modified mice and define AR-dependent programmatic changes in bPSC linked both to proliferation and epithelial hyperplasia.