Regulation of prostate epithelial basal cell plasticity

项目摘要 前列腺炎是男性常见的尿路问题。尽管病理性和流行病学 研究已将前列腺炎与前列腺癌的发生联系起来，其分子机制仍然存在 不清楚。回答这个问题将对前列腺癌的预防和早期干预具有临床益处。 已经提出，炎症可以诱导组织干细胞的扩张，从而扩大细胞 致癌转化池。在前列腺中，上皮性基底细胞在 器官发生和损伤修复，但在成年动态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人基底细胞以促进基底部到管腔的分化，从而促进 前列腺癌的发生和发展。这个项目的目标是阐明这些机制。 调节前列腺炎的基底细胞可塑性，并将相关知识应用于前列腺癌预防。我们的中央 假说是雄激素受体(AR)和Wnt信号的失调通过增加 WNT/β-连环蛋白活性降低和AR封存不足是基础细胞重新激活的主要因素 前列腺炎。在三个具体目标中，我们将使用小鼠遗传学的综合方法，活体血统追踪， 前列腺组织培养、芯片序列、生物化学、单细胞RNA序列和生物信息学来确定AR 和前列腺炎基底层细胞中的β-连环蛋白胞质是炎性间质环境的特征 对增强基础WNT活性至关重要，并评估WNT抑制的有效性 延缓前列腺炎引发的癌症。这个项目将提供新的洞察力，以了解 前列腺炎和前列腺癌，这是该领域的一个长期问题。研究成果将会是积极的 影响人类健康，因为Wnt信号是一个可用药的靶点，它的抑制是一个潜在的前景 改善前列腺炎引起的癌症进展的治疗。

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.