Mechanisms regulating prostate epithelium maintenance and regeneration

描述（由申请人提供）：鉴定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定前列腺癌发展和增殖中涉及的细胞类型和分子变化至关重要。 p63基因选择性地表达于各种上皮的基底细胞中，并且是上皮发育所必需的。最近已经显示p63对于胸腺上皮和表皮中的干细胞的增殖潜能是必需的。我们小组和其他人以前的工作表明，在正常的前列腺发育过程中，分泌细胞来源于p63阳性的基底细胞，因此代表祖细胞/干细胞。然而，在出生后的生活中，前列腺上皮在体内维持的机制仍有待澄清。基底细胞和分泌性前列腺细胞在发育过程中有层次关系的建议提出了一种可能性，即成年前列腺的更新依赖于p63阳性的基底干细胞。虽然来自体内和体外研究的数据为这种可能性提供了支持，但对比模型提出，成体分泌细胞能够维持自身的更新，而没有基底干细胞的显著贡献。 本申请中提出的实验旨在阐明生理条件下和细胞损伤后成人前列腺上皮的更新过程。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在体内重复分裂以产生有丝分裂后细胞的特化干/祖细胞（Aim 1）。在一个平行和互补的努力，我们将进行遗传谱系追踪，以确定是否在体内的前列腺上皮细胞的发育和更新依赖于p63阳性祖细胞/干细胞（目标2）。最后，我们将开始研究前列腺干细胞调控的分子机制，通过检验p63在调节前列腺干细胞功能中起核心作用的假设（目的3）。 我们的建议将提供非常有价值的知识的方式正常前列腺上皮细胞的发展，并在体内更新。这些知识对于未来识别前列腺癌发展和进展中涉及的细胞类型和分子异常是绝对需要的。 公共卫生相关性：前列腺由两种主要类型的细胞组成，即基底细胞和分泌细胞。已经提出基底细胞产生分泌细胞，因此代表干细胞。然而，前列腺上皮的维持方式尚不清楚。 在这个提议中，我们计划确定成年前列腺上皮的再生是否依赖于基底干细胞的增殖。此外，我们将研究调节干细胞功能的机制。 这些研究将为了解正常前列腺细胞如何形成和分化提供非常重要的知识。这些知识将揭示前列腺癌的起源细胞，因此，将大大有助于前列腺癌领域的进步。

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.