Impact of Inflammation on Adult Prostate Stem Cells

炎症对成体前列腺干细胞的影响

• 批准号: 10439754
• 负责人: Timothy L. Ratliff
• 金额: $ 59.47万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439754
• 关键词: Adult; Androgen Receptor; Antibodies; Automobile Driving; Benign Prostatic Hypertrophy; Cell Differentiation process; Cell Proliferation; Cells; Characteristics; Chronic; Critical Pathways; Data; Data Reporting; Development; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Foundations; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Growth; Growth Factor; Homeostasis; Hyperplasia; IL1R1 gene; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-1 alpha; Laboratories; Link; Molecular; Mus; Natural regeneration; Nuclear; Organoids; Pathway interactions; Phosphorylation; Phosphorylation Site; Prostate; Prostatic hypertrophy; Recombinants; Regulation; Reporting; Role; S-Phase Fraction; Signal Transduction; Stromal Cells; Structure of capsule of prostate; Testing; Tissues; Work; Yin-Yang; anakinra; autocrine; base; cell growth; cytokine; enzalutamide; genetic signature; in vivo; inhibitor; morphogens; novel; novel strategies; progenitor; prostate enlargement; receptor expression; receptor function; repaired; self-renewal; stem cell expansion; stem cell proliferation; stem cells

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.

良性前列腺增生（BPH）是指前列腺内上皮细胞和基质细胞的扩张。 尽管早期 BPH 中基质细胞扩张较多，但上皮细胞在前列腺移行区。 增生是导致较大症状性 BPH 前列腺的一个重要因素，而许多研究已将其联系起来。 慢性和顽固性炎症会导致 BPH 的发生，这是炎症导致 BPH 的机制 目前尚不清楚炎症会产生微环境。 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发生素， 包括基础前列腺干细胞 (bPSC) 控制和限制炎症的调节机制。 正常稳态条件下诱导的上皮细胞增殖尚未得到很好的定义，并且代表了 在理解炎症、不受控制的细胞生长和炎症之间的潜在联系方面存在重大缺陷 本文报道的数据确定了控制前列腺上皮细胞扩张和的途径。 为拟议的研究奠定基础，以更好地确定炎症诱导的前列腺的调节 上皮细胞增殖导致增生。了解炎症所涉及的途径。 诱导的细胞扩增将为开发阻断新方法提供基础 不受控制的上皮生长。 成体基底前列腺干细胞 (bPSC) 是维持和修复前列腺细胞完整性的特殊细胞。 前列腺；然而，描述炎症对成人 bPSC 影响的研究有限。 我们实验室的研究表明，炎症刺激 bPSC 扩张并产生基底细胞和管腔细胞 与离体非炎症（天然）bPSC 相比，体内上皮增生以及更大的类器官， 鉴于炎症驱动 bPSC 进入管腔，证明了这些细胞的持续增殖作用。 细胞转变，需要雄激素受体 (AR) 和此处报告的稳定炎症的数据 AR 通过磷酸化和 IL-1α 及其天然抑制剂 IL-1ra，其中 IL-1α 抑制 AR 表达 IL1ra 增强表达，导致 bPSC 驱动的上皮细胞扩增。 坚持认为炎症驱动 AR 稳定，从而驱动 bPSC 扩张和上皮细胞 为了检验该假设，我们建议定义炎症诱导的分子基础。 AR 稳定性，使用新型转基因小鼠评估通路影响并定义 AR 依赖性 bPSC 的程序性变化与增殖和上皮增生有关。