Mechanisms regulating prostate epithelium maintenance and regeneration

描述（由申请人提供）：鉴别调节正常前列腺上皮发育和维持的干细胞和分化程序对于鉴别参与前列腺癌发展和繁殖的细胞类型和分子变化至关重要。p63基因在各种上皮的基底细胞中选择性表达，是上皮发育所必需的。P63最近被证明对胸腺上皮和表皮干细胞的增殖潜能至关重要。我们小组和其他人之前的工作表明，在正常的前列腺发育过程中，分泌细胞来源于p53阳性的基底细胞，因此代表祖细胞/干细胞。然而，产后前列腺上皮在体内维持的机制仍有待阐明。基底和分泌性前列腺细胞在发育过程中具有等级关系，这一观点提出了一种可能性，即成人前列腺的更新依赖于p53阳性的基底干细胞。虽然体内和体外研究的数据都支持这种可能性，但一个对比模型表明，成人分泌细胞能够维持自身的更新，而无需基底干细胞的显著贡献。本实验旨在阐明成人前列腺上皮在生理状态和细胞损伤后的更新过程。我们将首先采用一种新的基于dna类似物的谱系追踪方法来测试成人前列腺上皮是否含有特化的干细胞/祖细胞，这些干细胞/祖细胞在体内反复分裂以产生有丝分裂后细胞（目的1）。在平行和互补的努力中，我们将进行遗传谱系追踪，以确定体内前列腺上皮的发育和更新是否依赖于p63阳性祖细胞/干细胞（目的2）。最后，我们将通过验证p63在调节前列腺干细胞功能中起核心作用的假设，开始研究前列腺干细胞调节的分子机制（目的3）。我们的研究将为正常前列腺上皮在体内的发育和更新提供极有价值的知识。这些知识对于未来确定参与前列腺癌发展和进展的细胞类型和分子异常是绝对必要的。

DESCRIPTION (provided by applicant): The identification of stem cells and differentiation programs regulating the development and maintenance of the normal prostate epithelium is essential for the identification of the cell type(s) and molecular changes involved in the development and propagation of prostate cancer. The p63 gene is selectively expressed in basal cells of various epithelia and is required for epithelial development. p63 has been recently shown to be essential for the proliferative potential of stem cells both in the thymus epithelium and the epidermis. Previous work from our group and others suggests that during normal prostate development, secretory cells derive from p63-positive basal cells, which thus represent progenitor/stem cells. However, the mechanisms underlying the in vivo maintenance of the prostate epithelium during post-natal life remain to be clarified. The suggestion that basal and secretory prostate cells are hierarchically related during development raises the possibility that the renewal of the adult prostate depends on p63-positive basal stem cells. While data from both in vivo and in vitro studies provide support for such a possibility, a contrasting model proposes that adult secretory cells are capable of sustaining their own renewal, without significant contribution from basal stem cells. The experiments proposed in this application are aimed at clarifying the renewal process of the adult prostate epithelium both in physiologic conditions and after cell injury. We will first employ a novel DNA-analog-based lineage tracing method to test whether the adult prostate epithelium contains specialized stem/progenitor cells that repeatedly divide in vivo to give rise to post-mitotic cells (Aim 1). In a parallel and complementary effort, we will perform genetic lineage tracing to determine whether the in vivo development and renewal of the prostate epithelium depends on p63-positive progenitor/stem cells (Aim 2). Finally, we will begin to study the molecular mechanisms of prostate stem cell regulation by testing the hypothesis that p63 plays a central role in modulating prostate stem cell functions (Aim 3). Our proposal will provide extremely valuable knowledge on the way the normal prostate epithelium develops and is renewed in vivo. Such knowledge is absolutely required for the future identification of the cell type(s) and molecular abnormalities involved in prostate cancer development and progression. PUBLIC HEALTH RELEVANCE: The prostate glands are composed of two main types of cells, i.e. basal and secretory cells. It has been proposed that the basal cells give rise to secretory cells and thus represent the stem cells. However, the way the prostate epithelium is maintained is unknown. In this proposal, we plan to establish whether the regeneration of the prostate epithelium in adult life depends on the proliferation of basal stem cells. In addition, we will study the mechanisms regulating stem cell functions. These studies will provide very important knowledge on how normal prostate cells form and differentiate. This knowledge will shed light on the cell of origin of prostate cancer and, therefore, will substantially contribute to the advancement of the prostate cancer field.