Determining the contribution of Sox2 to prostate stem cell activity and benign prostate hyperplasia

确定 Sox2 对前列腺干细胞活性和良性前列腺增生的贡献

• 批准号: 10022109
• 负责人: Daniel Clark Moline
• 金额: $ 2.44万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-04 至 2020-12-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022109
• 关键词: Adult; Androgens; Atlases; Behavior; Benign Prostatic Hypertrophy; Biological Markers; Castration; Catalogs; Cell Survival; Cells; Chronic; Communities; Data; Development; Disease; Embryo; Epithelial; Epithelial Cells; Epithelium; Genetic; Goals; Growth; Health; Homeostasis; Hormones; Human; Hyperplasia; Intestines; Knowledge; Location; Mediator of activation protein; Mentors; Mission; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Neoplasms; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Prevention; Process; Proliferating; Prostate; Prostatic hypertrophy; Proteins; Public Health; Publishing; Quality of life; Research; Research Personnel; Role; Signal Transduction; Stem Cell Factor; Surface; Testing; Therapeutic; Tissues; Treatment Protocols; United States National Institutes of Health; Urethra; Work; constriction; epithelial stem cell; experimental study; human disease; improved; innovation; insight; lower urinary tract symptoms; men; neoplastic; new technology; new therapeutic target; pluripotency; programs; reduce symptoms; restoration; self-renewal; single-cell RNA sequencing; stem; stem cell population; stem cells; theories; therapeutic target; tissue regeneration; transcription factor; transcriptome; urologic

Abstract: The adult human prostate is normally quiescent and does not produce new tissue at an appreciable rate. When this state of quiescence is broken, the prostate epithelium undergoes hyperplastic growth in a chronic condition referred to as benign prostatic hyperplasia. Although hyperplastic growth of the prostate is a common ailment, little is known about the specific epithelial stem cell populations that are thought to contribute to the disease. Prostate epithelial stem cells are marked by multipotency, self-renewal, and tissue regeneration as well as a unique independence of androgen signaling not seen in differentiated prostate epithelial cells. Data from the mentor’s lab shows that the transcription factor Sox2 is expressed during prostate development as well as in a rare population of cells in the adult prostate. Genetic lineage tracing data show that Sox2+ cells persist in the absence of androgen signaling and contribute to new epithelial tissue during prostate regeneration. Although these data imply that Sox2+ cells are epithelial stem cells, a direct experimental approach must be used to define their place in the lineage hierarchy of the prostate as well as the genetic program employed by Sox2 to yield this phenotype. A deeper understanding of the identity and underlying mechanisms of stem cell populations within the prostate epithelium is necessary for the development of improved treatments for prostatic hyperplasia targeting stem cell populations. The scientific objective of this application is to establish the contribution of Sox2 to prostate regeneration. This proposal is innovative because it will be the first to test the necessity of Sox2 in the process of prostate regeneration, as well as being one of the first to catalog the single-cell transcriptomes of a castrate and intact prostate simultaneously for direct comparison. This proposal is significant because it will establish the role of a known stem cell factor in the hierarchy and processes of the prostate epithelium. This will allow for the new therapeutic targets in the effort to create improved treatment regimens for benign prostatic hyperplasia.

摘要： 成年人前列腺通常是静止的，并且在正常情况下不产生新组织。 可观的利率。当这种静止状态被打破时，前列腺上皮经历 在称为良性前列腺增生的慢性病症中的增生性生长。虽然 前列腺增生是一种常见的疾病，但对前列腺增生的具体机制知之甚少。 上皮干细胞群被认为有助于疾病。前列腺上皮 干细胞具有多能性、自我更新和组织再生的特点， 在分化的前列腺上皮细胞中未观察到雄激素信号传导的独特独立性。 导师实验室的数据显示，转录因子Sox 2在前列腺增生期间表达， 在成年前列腺中的一种罕见的细胞群体中也是如此。遗传谱系追踪 数据显示，Sox 2+细胞在雄激素信号传导缺乏的情况下持续存在，并有助于新的 前列腺再生过程中的上皮组织。尽管这些数据暗示Sox 2+细胞是 上皮干细胞，必须使用直接的实验方法来定义它们在细胞中的位置 前列腺的谱系层级以及Sox 2所采用的遗传程序来产生这一点。 表型更深入地了解干细胞的身份和潜在机制 前列腺上皮内的细胞群对于改善的前列腺增生的发展是必要的。 前列腺增生的治疗靶向干细胞群体。的科学目标 本申请旨在确定Sox 2对前列腺再生的贡献。这项建议是 创新，因为它将是第一个测试Sox 2在前列腺增生过程中的必要性。 再生，也是最早对单细胞转录组进行编目的人之一 去势和完整的前列腺同时进行直接比较。这一提议意义重大 因为它将建立一个已知的干细胞因子在分级和过程中的作用， 前列腺上皮这将允许新的治疗目标， 改善良性前列腺增生的治疗方案。