Function of the Stem Cell Transcription Factor SOX2 in Prostatic Enlargement

项目概要/摘要： 与许多经历与年龄相关的退化的器官不同，前列腺经历年龄- 在大多数60岁以上的男性中， 岁越来越多的证据表明，前列腺干/祖细胞的核心作用， 前列腺再生途径的异常激活导致前列腺增大。 目前前列腺肥大的治疗方法主要围绕治疗 靶向雄激素受体（AR），可以部分缓解症状，但不能达到 永久性疾病缓解。我们的实验室最近确定了重要的干细胞 因子SOX 2是前列腺发育过程中重要的干/祖细胞和存活因子 和再生。SOX 2是维持生存所必需的转录因子， 胚胎干细胞和许多成体干细胞的多能性，并与OCT 4典型地相互作用， 促进干细胞基因表达并抑制分化。该提案基于 我们的工作证明了一个重要的和新的非干细胞和前列腺特异性 SOX 2在前列腺中的功能，从而SOX 2促进对AR靶向的 治疗和干/祖细胞扩增以促进前列腺增大。 然而，在我们对SOX 2的机制作用的理解方面仍然存在重大差距。 前列腺肥大;填补这样的知识空白有很高的潜力，功能牵连 SOX 2和SOX 2靶基因作为预防和治疗年龄相关疾病的新靶点 前列腺肥大这个项目的长期目标是确定信号通路 在前列腺上皮细胞中由SOX 2调节，可以靶向预防和治疗 治疗前列腺肥大。目的是确定SOX 2如何促进 多能前列腺上皮细胞，并有助于前列腺干细胞扩增腺 并开始测试耗尽前列腺祖细胞群的新策略。 我们的中心假设是，SOX 2阳性前列腺细胞的数量增加， 衰老，而SOX 2能够抵抗AR靶向治疗，从而促进前列腺 放大

Project Summary/Abstract: Unlike many organs that undergo age-related degeneration, the prostate gland undergoes age- related enlargement leading to significant health complications in the majority of men over 60 years old. Increasing evidence indicates a central role for prostate stem/progenitor cells and abnormal activation of prostate regeneration pathways leading to prostate enlargement. Current treatment approaches for prostatic enlargement primarily revolve around therapies targeting the androgen receptor (AR), which can partially alleviate symptoms but do not achieve permanent disease remission. Our laboratory recently determined that the important stem cell factor SOX2 is an important stem/progenitor and survival factor during prostate development and regeneration. SOX2 is a transcription factor that is essential for maintaining survival and pluripotency of embryonic and many adult stem cells, and canonically interacts with OCT4 to promote stem cell gene expression and repress differentiation. This proposal builds upon our work demonstrating an important and novel non-stem cell and prostate-specific function for SOX2 in the prostate, whereby SOX2 promotes resistance to AR-targeted therapies and expansion of stem/progenitor cells to promote prostate enlargement. However, there remain significant gaps in our understanding of the mechanistic role of SOX2 in prostate enlargement; filling such knowledge gaps has a high potential to functionally implicate SOX2 and SOX2-target genes as new therapeutic targets to prevent and treat age-related prostate enlargement. The long-term goal of this project is to identify signaling pathways regulated by SOX2 in prostate epithelial cells that can be targeted to prevent and therapeutically treat prostate enlargement. The objective is to define how SOX2 promotes the survival of multipotent prostate epithelial cells and contributes to prostate stem cell expansion glandular enlargement and begin testing novel strategies to deplete prostate progenitor cell populations. Our central hypothesis is that the quantity of SOX2-positive prostate cells increases during aging, and SOX2 enables resistance to AR-targeted therapies, thereby promoting prostate enlargement.