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）是指前列腺内上皮细胞和间质细胞的增生