Androgen Signaling in Prostatic Sonic Hedgehog Responsive Cells

前列腺 Sonic Hedgehog 反应细胞中的雄激素信号传导

• 批准号: 10295736
• 负责人: ZIJIE SUN
• 金额: $ 38.72万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295736
• 关键词: AR gene; Address; Adult; Affect; Androgen Receptor; Androgens; Benign Prostatic Hypertrophy; Biological; Biological Assay; Bladder; Castration; Cell Differentiation process; Cells; Complete Androgen-Insensitivity Syndrome; Complex; Data; Development; Differentiation and Growth; Disease; Embryo; Embryonic Development; Endocrine Glands; Epithelial; Future; Growth; Growth Factor; Healthcare Systems; Homeostasis; Human; Knowledge; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchyme; Morbidity - disease rate; Morphogenesis; Mus; Mutation; Natural regeneration; Neck; Pathogenesis; Play; Property; Prostate; Prostatic; Prostatic Epithelium; Puberty; Receptor Activation; Receptor Signaling; Research; Resistance; Role; SHH gene; Series; Signal Pathway; Signal Transduction; Stromal Cells; Testing; Time; Tissue Recombination; Urethra; Urogenital Sinus; Withdrawal; aging population; base; effective therapy; experimental study; insight; male; mouse genetics; mouse model; paracrine; pluripotency; postnatal; prepuberty; progenitor; prostatitis; reproductive; smoothened signaling pathway; stem; stem cell niche; stem cells; tool

PROJECT SUMMARY The androgen-signaling pathway mediated through the androgen receptor is essential for prostate embryonic development, prepubescent morphogenesis, and pubertal growth and regeneration. Mutation of the Ar gene in testicular feminized mice results in the complete absence of prostate development. During embryogenesis, the AR is initially detected in the urogenital sinus mesenchyme prior to the initiation of prostate budding and morphogenesis, and its expression extends to the urogenital sinus epithelium after the initiation of prostatic budding and branching morphogenesis. Early tissue recombination assays done more than 30 years ago demonstrated that mesenchymal, rather than epithelial AR signaling plays a decisive role in inducing development of the prostatic epithelium, providing the first scientific evidence for a stromal cell niche in supporting prostate stem cell initiated prostate early development. Androgen signaling still remains essential for prostatic postnatal morphogenesis, growth and regeneration. Prostatic regeneration through repeated cycles of androgen withdrawal and replacement further demonstrates the essential role of androgen signaling in prostate cell differentiation and growth. However, despite significant research effort in the past 30 years, the underlying mechanisms by which androgens facilitate prostatic stem/progenitor cells through paracrine interactions between prostatic epithelium and mesenchyme are largely unknown. Specifically, the cellular properties of the AR-expressing mesenchymal cells that can convey androgen signaling to regulate prostatic epithelial development and morphogenesis still remain unclear. Sonic hedgehog signaling plays a critical role in prostate development, homeostasis, and regeneration through mesenchymal–epithelial interactions. The Shh growth factors and its downstream effectors are expressed in either prostatic epithelial or mesenchymal cells, respectively, during embryogenesis and adulthood. Recently, using mouse genetic tools, we demonstrate for the first time that selective deletion of AR in mesenchymal Gli1-expressing cells abolishes prostatic embryonic development and prostate formation, and diminishes prostate pubertal growth and regeneration. In addition, results from our tissue recombination assays showed that mesenchymal AR and Gli1 expressing cells act as cell niches in supporting prostate early development and prostatic gland formation. These findings provide fresh insight into the cellular identity of the stromal cell niche in supporting prostate stem/progenitor function in the prostate, and implicate a new regulatory mechanism for stromal androgen and Shh signaling in regulating prostatic cell fate, growth, and renewal. Based on these new and significant findings, we propose a series of experiments to test our central hypothesis: stromal androgen signaling in Shh-responsive cells acts as a stem cell niche and plays an essential role for prostate early development, prepubescent morphogenesis, and pubertal growth and regeneration.

项目摘要 通过雄激素受体介导的雄激素信号途径对于前列腺至关重要 胚胎发育，预性形态发生以及青春期的生长和再生。突变 在有效的女性小鼠中，AR基因完全没有前列腺发育。期间 胚胎发生，最初在泌尿生殖器窦间充质中检测到AR，然后再进行前列腺 发芽和形态发生，其表达延伸至泌尿生殖器窦上皮。 前列腺萌芽和分支形态发生。早期组织重组测定已完成了30多年 AGO证明间质，而不是上皮AR信号在诱导中起决定性作用 前列腺上皮的发展，为基于基质细胞生态位的第一个科学证据提供 支持前列腺干细胞引发了前列腺早期发育。雄激素信号仍然至关重要 用于产后形态发生，生长和再生。通过重复再生 雄激素提取和替换的循环进一步证明了雄激素信号的重要作用 在前列腺细胞分化和生长中。然而，尽管过去30年中的研究工作很大，但 雄激素通过旁分泌促进前列腺茎/祖细胞的潜在机制 前列腺上皮和间质之间的相互作用在很大程度上未知。具体而言，细胞 表达AR的间充质细胞的性质，这些细胞可以传达雄激素信号传导以调节前列腺 上皮发育和形态发生仍然不清楚。 声音刺猬信号在前列腺发展，体内平衡和再生中起着至关重要的作用 通过间质 - 上皮相互作用。 SHH增长因素及其下游影响是 在胚胎发生和 成年。最近，使用鼠标遗传工具，我们首次证明了AR的选择性删除 在间充质Gli1的表达细胞中，前列腺胚胎发育和前列腺形成，以及 减少前列腺青春期的生长和再生。此外，我们的组织重组的结果 测定表明，间充质AR和GLI1表达细胞在早期支撑前列腺的细胞壁细胞 发育和前列腺形成。这些发现为细胞身份提供了新的见解 在支持前列腺中支持前列腺茎/祖细胞功能方面的基质细胞生态位，并暗示了一个新的 调节性前列腺细胞脂肪，生长和 更新。基于这些新的和重要的发现，我们提出了一系列实验来测试我们的中央 假设：SHH响应细胞中的基质雄激素信号传导充当干细胞生态位，并发挥作用 前列腺早期发育，青春期前形态发生和青春期的生长以及 再生。