The Prostate Epithelial Cell Lineage Hierarchy

描述(申请者提供)：本资助申请旨在了解前列腺上皮分化的基本生物学。哺乳动物组织是由以分层方式组织的细胞组成的，包括干细胞、定向祖细胞和终末分化细胞。解剖组织谱系将有助于确定在发育和疾病中发挥关键作用的分子信号通路。前列腺上皮细胞的谱系在很大程度上仍未确定。尽管已经确定了两种不同类型的多潜能前列腺干细胞，但干细胞如何分化并产生终末分化的细胞系仍不清楚。这项资助提案关注的是前列腺干细胞如何产生占前列腺上皮细胞90%以上的前列腺腔上皮细胞这一普遍问题。我们的目标是研究前列腺腔细胞系是如何维持的，以及雄激素受体在不同的上皮细胞系中在上皮细胞分化过程中所扮演的角色。我们的初步数据表明，腔细胞在表型和功能上是不同的，并支持长期以来存在的关于存在雄激素非依赖性前列腺腔前体细胞的假说。采用遗传学和细胞学相结合的方法，我们将(1)确定前列腺腔细胞系如何在体内维持；(2)根据其抗原表达谱分离前列腺腔前体细胞；(3)研究雄激素受体在不同前列腺上皮细胞系中的生物学作用。

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.