The Prostate Epithelial Cell Lineage Hierarchy

描述（由申请人提供）：本资助申请旨在了解前列腺上皮分化的基本生物学。哺乳动物组织由分层组织的细胞组成，包括干细胞、承诺祖细胞和终末分化细胞。解剖组织谱系层级将有助于识别在发育和疾病中起关键作用的分子信号通路。前列腺上皮细胞的谱系等级在很大程度上仍未明确。虽然已经确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最终分化的细胞系仍不清楚。这项拨款提案的重点是前列腺干细胞如何产生占前列腺上皮90%以上的前列腺腔上皮细胞的一般问题。我们的目的是研究前列腺腔细胞系是如何维持的，以及雄激素受体在上皮细胞分化过程中不同上皮细胞系的作用。我们的初步数据表明，管腔细胞在表型和功能上是异质的，并支持长期存在的雄激素不依赖性前列腺管腔祖细胞群体存在的假设。使用遗传和细胞方法的结合，我们将(1)确定前列腺腔细胞谱系如何在体内维持；(2)根据前列腺腔祖细胞抗原表达谱分离前列腺腔祖细胞；(3)探讨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.