The Prostate Epithelial Cell Lineage Hierarchy

描述（由申请人提供）：本基金申请旨在了解前列腺上皮分化的基础生物学。哺乳动物组织由以分级方式组织的细胞组成，包括干细胞、定向祖细胞和终末分化细胞。解剖组织谱系层次将有助于确定在发育和疾病中起关键作用的分子信号传导途径。前列腺上皮谱系在很大程度上仍不明确。虽然已经鉴定了两种不同类型的多能前列腺干细胞，但干细胞如何分化并产生终末分化的细胞谱系仍不清楚。这项拨款提案的重点是前列腺干细胞如何产生前列腺腔上皮细胞，构成超过90%的前列腺上皮细胞的一般问题。我们的目标是研究前列腺腔细胞谱系是如何维持的，以及雄激素受体在不同上皮细胞谱系沿着上皮细胞分化中的作用。我们的初步数据表明，管腔细胞是表型和功能异质性的，并支持长期存在的假设，即存在雄激素非依赖性前列腺管腔祖细胞的群体。使用遗传和细胞方法的组合，我们将（1）确定前列腺腔细胞谱系如何在体内维持;（2）基于其抗原表达谱分离前列腺腔祖细胞;（3）研究雄激素受体在不同前列腺上皮细胞谱系中的生物学作用。 公共卫生相关性：前列腺相关疾病，包括良性前列腺增生和前列腺癌，是男性的主要健康问题。我们提出的研究是揭示在这些疾病的发生和发展中起关键作用的分子信号通路的重要先决条件，并最终将对其诊断和治疗产生重大影响。

DESCRIPTION (provided by applicant): This grant application aims to understand basic biology of prostate epithelial differentiation. Mammalian tissues are composed of cells organized in a hierarchical manner, including stem cels, committed progenitors, and terminally differentiated cells. Dissecting the tissue lineage hierarchy will help identify molecular signaling pathways that play key roles in development and diseases. The prostate epithelial lineage hierarchy remains largely undefined. Though two distinct types of multipotent prostate stem cells have been identified, it remains unclear how stem cells differentiate and generate terminally differentiated cell lineages. This grant proposal is focused on the general question of how prostate stem cells give rise to prostate luminal epithelial cells that constitutes more than 90% of prostate epithelia. Our goals are to investigate how the prostate luminal cell lineage is sustained and what the roles are of the androgen receptor in different epithelial cell lineages along epithelial cell differentiation. Our preliminary data suggest that luminal cells are phenotypically and functionally heterogeneous and support the long-existing hypothesis of the existence of a population of androgen- independent prostate luminal progenitors. Using a combination of genetic and cellular approaches, we will (1) determine how the prostate luminal cell lineage is sustained in vivo; (2) isolate prostate luminal progenitor cells based on their antigenic expression profiles; (3) investigate the biological role of the androgen receptor in different prostate epithelial cell lineages. PUBLIC HEALTH RELEVANCE: Prostate related diseases, including benign prostatic hyperplasia and prostate cancer, represent major health problems for men. Our proposed studies are important prerequisites to unveil molecular signaling pathways that play critical roles in initiation and progression of these diseases, and will eventually have a major impact on their diagnosis and therapeutics.