Regulation of prostate epithelial basal cell plasticity

 描述（由申请人提供）：成体干细胞在响应细胞环境时表现出其多能能力的显著可塑性，这对于其在器官发育和组织稳态中的功能至关重要。在哺乳动物中，了解成体干细胞可塑性是如何调节的，一直受到复杂的细胞组织和不充分的工具来解剖体内细胞相互作用的阻碍。在这里，我们建议在小鼠前列腺上皮中解决这个问题，这是一个很好的系统，用于研究干细胞调控的机制，因为它具有明确的细胞谱系层次结构和新颖的遗传工具。我们发现前列腺基底细胞在不同的发育阶段和生理环境中具有不同的多能性，这使我们关注细胞外信号和腔-基底细胞相互作用在调节基底细胞可塑性中的作用。在 三个具体的目标，我们将剖析在基底细胞的信号通路的发育阶段依赖性的相互作用;确定管腔细胞调节基底细胞的行为的机制;并确定基底细胞增殖如何影响其管腔分化。为了实现我们的目标，我们将采取离体组织重建，高通量分子分析和遗传谱系追踪的综合方法，其中遗传操作和细胞行为分析可以在体内天然组织环境中在单个细胞水平上同时进行。鉴于基底细胞和腔细胞共同塑造了许多上皮组织的组织，并且它们的失调通常先于癌症的发生，我们的研究将为上皮组织的发育和维持提供重要的见解，并将对理解疾病病因学产生重要影响。

 DESCRIPTION (provided by applicant): Adult stem cells demonstrate significant plasticity of their multipotent capabilities in response to cellular environment, and this is crucial for their functions in organ development and tissue homeostasis. In mammals, understanding how adult stem cell plasticity is regulated has been hampered by the complex cell organization and inadequate tools to dissect cellular interactions in vivo. Here, we propose to address this question in the mouse prostate epithelium, an excellent system for investigating the mechanism of stem cell regulations due to its well-defined cell lineage hierarchy and novel genetic tools available. Our discovery of the distinct multipotent capabilities of prostate basal cells in differnt developmental stages and physiological contexts has led us to focus on the roles of extracellular signaling and luminal-basal cell interactions in regulating basal cell plasticity. In three specific aims, we will dissect the developmental stage-dependent interplay of signaling pathways in basal cells; identify the mechanisms by which luminal cells regulate basal cell behaviors; and determine how basal cell proliferation affects its luminal differentiation. To achieve our goals, we will take an integrated approach of ex vivo tissue reconstitution, high-throughput molecular profiling, and genetic lineage tracing, in which genetic manipulation and cell behavior analysis can be simultaneously performed at individual cell level in native tissue environment in vivo. Given that basal and luminal cells together shape the organization of many epithelial tissues and that their dysregulation often precedes cancer initiation, our studies will provide significant insights into the development and maintenance of epithelial tissues, and will have important implications for understanding disease etiology.