Regulation of prostate epithelial basal cell plasticity

项目摘要 前列腺炎是男性常见的泌尿系统疾病。虽然病理学和流行病学 研究表明前列腺炎与前列腺癌的发生有关，但其分子机制仍然存在。 不清楚解决这个问题将对前列腺癌的预防和早期干预具有临床意义。 已经提出炎症可以诱导组织干细胞扩增，从而扩大细胞体积， 致癌转化池。在前列腺中，上皮基底细胞在前列腺增生期间充当干细胞。 器官发生和损伤修复，但在成人体内平衡中处于静止状态。小鼠模型中的初步数据 提示前列腺炎重新激活成年基底细胞，促进基底细胞向管腔分化， 前列腺癌的发生和发展。本项目的目标是阐明 调节前列腺炎的基底细胞可塑性，并将这些知识应用于前列腺癌的预防。我们的中央 假设是雄激素受体（AR）和Wnt信号传导串扰失调通过增加 Wnt/β-catenin活性和AR隔离不足是基底细胞再激活的主要因素， 前列腺炎在三个具体目标中，我们将使用小鼠遗传学，体内谱系追踪， 前列腺类器官培养、ChIP-seq、生物化学、单细胞RNA-seq和生物信息学，以确定AR 和β-连环蛋白顺式组在前列腺炎基底细胞中的表达，表征了炎症基质环境 对于基础Wnt活性的增强至关重要，并评估Wnt抑制在 延缓肠炎引发的癌症该项目将提供新的见解之间的机械联系 前列腺炎和前列腺癌，这是该领域长期存在的问题。研究成果将积极 影响人类健康，因为Wnt信号传导是一个可药物靶点， 用于改善结肠炎诱导的癌症进展的治疗。

Project Summary Prostatitis is a common urinary tract problem for men. Although pathological and epidemiological studies have linked prostatitis to the development of prostate cancer, its molecular mechanism remains unclear. Answering this question will have clinical benefits in prostate cancer prevention and early intervention. It has been proposed that inflammation can induce tissue stem cell expansion, thereby enlarging the cellular pool for oncogenic transformation. In the prostate, epithelial basal cells serve as stem cells during organogenesis and injury repair, but are quiescent in adult homeostasis. Preliminary data in mouse models suggest that prostatitis reactivates adult basal cells to promote basal-to-luminal differentiation, which facilitates the initiation and progression of prostate cancer. The goal of this project is to elucidate the mechanisms regulating basal cell plasticity in prostatitis and apply the knowledge for prostate cancer prevention. Our central hypothesis is that dysregulation of the androgen receptor (AR) and Wnt signaling crosstalk through an increase of Wnt/β-catenin activity and insufficient AR sequestration is a major factor underlying basal cell reactivation in prostatitis. In three specific aims, we will use an integrated approach of mouse genetics, in vivo lineage tracing, prostate organoid culture, ChIP-seq, biochemistry, single cell RNA-seq, and bioinformatics to determine the AR and β-catenin cistromes in basal cells in prostatitis, characterize the inflammatory stromal environment essential for the enhancement of basal Wnt activities, and assess the effectiveness of Wnt inhibition in delaying prostatitis-stimulated cancer. This project will provide novel insights into the mechanistic link between prostatitis and prostate cancer, a long-standing question in the field. The research outcomes will positively impact human health since Wnt signaling is a druggable target and its inhibition is a potentially promising treatment for ameliorating prostatitis-induced cancer progression.