Function of the Stem Cell Transcription Factor SOX2 in Prostatic Enlargement

干细胞转录因子 SOX2 在前列腺肥大中的作用

• 批准号: 10305692
• 负责人: Donald James Vander Griend
• 金额: $ 50.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305692
• 关键词: Aging; Alternative Therapies; Androgen Receptor; BCL2 gene; Binding; Castration; Cell Differentiation process; Cell Survival; Cells; ChIP-seq; Data; Development; Disease Resistance; Disease remission; EZH2 gene; Embryo; Epithelial Cells; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Health; Histologic; Hormones; Human; Knowledge; Laboratories; Life Expectancy; Mediating; Multipotent Stem Cells; Mus; Natural regeneration; Organ; Pathway interactions; Patients; Pharmacology; Population; Prevention; Prostate; Prostatic; Publishing; Regenerative pathway; Regulation; Resistance; Role; Signal Pathway; Specimen; Stem Cell Factor; Testing; Therapeutic; Tissues; Transgenic Mice; Work; adult stem cell; age related; lower urinary tract symptoms; member; men; mouse model; new therapeutic target; novel; novel strategies; pluripotency; prevent; progenitor; prostate enlargement; reduce symptoms; single-cell RNA sequencing; stem; stem cell expansion; stem cell function; stem cell genes; stem cells; targeted treatment; therapy resistant; transcription factor; transcriptome sequencing

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.

项目摘要/摘要： 与许多与年龄相关的退化器官不同，前列腺癌经历的是年龄- 相关的肥大导致大多数60岁以上男性出现严重的健康并发症 很多年了。越来越多的证据表明，前列腺干细胞/祖细胞和 前列腺再生通路异常激活导致前列腺肥大。 目前治疗前列腺增大症的方法主要围绕治疗方法。 靶向雄激素受体(AR)，可以部分缓解症状，但不能达到 永久的疾病缓解。我们的实验室最近确定了重要的干细胞 SOX2因子是前列腺发育过程中重要的干/祖细胞和存活因子 和再生。SOX2是一种转录因子，对维持生存和 胚胎干细胞和许多成体干细胞的多能性，并与OCT4典型地相互作用 促进干细胞基因表达，抑制分化。这项建议的基础是 我们的工作展示了一种重要而新颖的非干细胞和前列腺特异性 SOX2在前列腺中的作用，通过SOX2促进对AR靶向的抵抗 治疗和扩增干细胞/祖细胞以促进前列腺增大。 然而，在我们对SOX2的机制作用的理解上仍然有很大的差距 前列腺增大；填补这样的知识空白很有可能在功能上隐含 SOX2和SOX2靶基因作为防治年龄相关性疾病的新靶点 前列腺肥大。该项目的长期目标是确定信号通路 受SOX2调控的前列腺上皮细胞可靶向预防和治疗 治疗前列腺肥大。其目标是定义SOX2如何促进人类生存 多能前列腺上皮细胞和促进前列腺干细胞扩大腺 并开始测试耗尽前列腺祖细胞数量的新策略。 我们的中心假设是SOX2阳性的前列腺细胞在 衰老，SOX2使人对AR靶向治疗产生抵抗，从而促进前列腺癌 放大。