Molecular mechanisms of prostate cancer initiation

项目总结（见说明）： 本计画将研究前列腺癌发生的分子机制.拟议的研究将由一个高度整合的跨学科研究团队进行，该团队在前列腺癌研究方面有大量的跟踪记录，并且彼此之间有合作互动。我们的建议主要集中在NKX3.1的作用上，NKX3.1是基因表达的关键调节因子。 在前列腺上皮中的程序，其表达在前列腺癌起始期间下调。 我们研究小组成员最近的研究表明，Nkx3.1是前列腺上皮干细胞群的标志物，前列腺上皮干细胞群是小鼠前列腺癌的起源细胞类型，并且Nkx3.1在干细胞维持中起作用。此外，NKX3.1参与了DNA损伤应答中涉及的最早期分子事件，而NKX3.1缺失倾向于增加氧化损伤，减少DNA损伤。 DNA损伤后的存活和细胞衰老。因此，NKX3.1在前列腺肿瘤发生中的功能分析代表了研究癌症起始的极好模型。 我们将开展三个相互关联的项目，这些项目将使用基因工程小鼠和细胞培养模型研究前列腺癌启动的分子机制，以及使用人类异种移植物和临床标本进行必要的验证。项目1（Shen）将在小鼠模型中研究前列腺癌的潜在起源细胞类型，并将确定这些起源细胞是否可以产生肿瘤起始细胞。项目2（Abate-Shen）将分析Nkx3.1在前列腺上皮特化和细胞衰老中的作用，并将通过全基因组分析结合小鼠和人类前列腺的功能验证来识别Nkx3.1靶基因。项目3（Gelmann）将研究Nkx3.1在细胞培养和小鼠模型中DNA损伤反应中的作用。这些项目将得到以下方面的协助： 核心A（Cordon-Cardo）将为项目提供病理学支持，并将检查前列腺癌启动中已知分子事件的发生率和共定位，核心B（Shen）将为整个项目提供行政、生物信息学和生物统计学支持。

PROJECT SUMMARY (See instructions): This Program Project application will Investigate the molecular mechanisms of prostate cancer initiation. The proposed studies will be pursued by a highly-integrated Interdisciplinary team of investigators who have substantial track records in prostate cancer research, as well as in collaborative interactions with each other. Our proposal has a central focus on the role of NKX3.1, a key regulator of gene expression programs in the prostate epithelium whose expression is down-regulated during prostate cancer initiation. Recent studies by members of our research team have shown that Nkx3.1 is a marker for a prostate epithelial stem cell population that is a cell type of origin for prostate cancer in mice, and that Nkx3.1 plays a role in stem cell maintenance. Furthermore, NKX3.1 participates in the earliest molecular events involved in the response to DNA damage, while NKX3.1 loss predisposes to increased oxidative damage, decreased survival after DNA damage, and cellular senescence. Thus, analysis of NKX3.1 function in prostate tumorigenesis represents an excellent model for investigating cancer initiation. We will pursue three interrelated projects that will investigate the molecular mechanisms of prostate cancer initiation using genetically-engineered mouse and cell culture models, together with essential validation using human xenografts and clinical specimens. Project 1 (Shen) will investigate the potential cell type(s) of origin for prostate cancer in mouse models, and will determine whether these cells of origin can give rise to tumor-initiating cells. Project 2 (Abate-Shen) will analyze the roles for Nkx3.1 in prostate epithelial specification and cellular senescence, and will identify Nkx3.1 target genes through genome-wide analyses coupled with functional validation in mouse and human prostate. Project 3 (Gelmann) will investigate the role of Nkx3.1 in the DNA damage response in cell culture and mouse models. These Projects will be assisted by Core A (Cordon-Cardo), which will provide pathology support for the Projects and will examine the incidence and co-localization of known molecular events in prostate cancer initiation, as well as by Core B (Shen), which will provide administrative, bioinformatic, and biostatistical support for the overall Program.