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: 10218167
• 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/10218167
• 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; genetic signature; in vivo; inhibitor/antagonist; 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）是由上皮细胞和基质细胞在 前列腺的过渡区。尽管在早期BPH中，基质细胞的扩张较大，但上皮 增生是引起较大症状BPH前列腺的重要原因。虽然许多研究已经连接 慢性和顽固注射BPH的发育，注射引线的机制 尚不清楚细胞增殖和增生。众所周知，注射会产生微环境 富含细胞因子，生长因子和其他形态因素，促进前列腺上皮细胞的增殖， 包括基本的前列腺干细胞（BPSC）。控制和限制炎症的调节机制 在正常稳态条件下诱导的上皮细胞增殖尚未很好地定义，并表示 理解炎症，不受控制的细胞生长和 前列腺膨胀。此处报告的数据确定了控制前列腺上皮细胞扩展的途径和 构成了拟议研究的基础，以更好地定义炎症诱导的前列腺的调节 导致增生的上皮细胞增殖。了解炎症涉及的途径 - 诱导的细胞膨胀将为开发新颖的方法奠定基础 不受控制的上皮生长。 成人碱性前列腺干细胞（BPSC）是维持和修复细胞完整性的专门细胞 前列腺；但是，描述炎症对成人BPSC的影响的研究受到限制。以前的数据 从我们的实验室中表明，感染刺激BPSC的扩展并产生基本和腔内 与非影响（幼稚的）bpsc Ex vivo相比 证明对这些细胞的持续增生剂作用。鉴于炎症将BPSC驱动到腔 细胞转变，需要雄激素受体（AR），并且在此报告的数据稳定炎症 通过磷酸化和IL-1α及其天然存在的抑制剂IL-1RA，IL-1α抑制AR表达 IL1RA增强了表达，导致上皮细胞的扩张。基于这些数据，我们 假设炎症驱动AR稳定化，从而驱动BPSC扩展和上皮 BPH中的增生。为了检验假设，我们建议定义炎症引起的分子基础 AR稳定，使用新颖的一般修饰的小鼠评估途径影响，并定义AR依赖性 BPSC的程序化变化与增殖和上皮增生有关。