Functional Annotation of the Pancreatic Cancer Genome

描述(由申请人提供)：在过去的十年里，我们对人类胰腺癌潜在的基因变化的理解取得了前所未有的进步。在项目研究人员的一系列重要贡献的领导下，胰腺癌的遗传和表观遗传学基础已被慢慢揭开，目前已有30多个遗传位点在这种疾病中发生突变，报道的编码基因和非编码microRNAs的基因表达发生了特征性变化。然而，这些突变对胰腺癌表型的功能贡献在很大程度上仍未得到研究。该计划项目赠款的中心目标是通过确定在人类胰腺癌中发现的分子变化的功能意义，缩小遗传数据和功能数据之间的差距。这一功能注释将通过研究候选显性和隐性突变的影响以及microRNA表达的特征变化来进行，使用我们小组成员开发的基于细胞、斑马鱼和小鼠的新分析方法。将执行四个项目：项目1：斑马鱼系统中人胰腺癌基因的功能注释(LEACH)；项目2：发现和评估人类胰腺癌的优先突变(KERN)；项目3：胰腺癌中的河马信号通路(Maitra)；以及项目4：胰腺肿瘤中microRNAs的功能评估(Mendell)。这些项目将得到三个共享核心的支持：核心A：细胞和转基因表型核心(HHISO)；核心B：斑马鱼核心(Parsons)；以及核心C：行政核心(LEACH)。从事这些项目的研究人员都是胰腺癌研究领域的领导者，并在协同作用方面有着出色的记录。该计划还利用了约翰霍普金斯大学现有的许多资源，包括NCI Gl孢子赠款的各个方面，约翰霍普金斯综合癌症中心提供的核心资源，以及独立资助的胰腺癌基因组计划。总之，这些研究将极大地加速胰腺癌基因组的功能注释，为未来的治疗应用奠定基础。

DESCRIPTION (provided by applicant): The past decade has witnessed unprecedented progress in our understanding of the genetic changes underlying human pancreatic cancer. Led by a long series of important contributions by Program investigators, the genetic and epigenetic basis for pancreatic cancer has slowly been unraveled, with over 30 genetic loci now recognized to undergo mutation in this disease, and characteristic changes in gene expression reported for an even larger number of coding genes and non-coding microRNAs. However, the functional contribution of these mutations to the pancreatic cancer phenotype remains largely uninvestigated. The central Aim of this Program Project Grant is to narrow the gap between genetic and functional data, by determining the functional significance of molecular alterations identified in human pancreatic cancer. This functional annotation will be pursued by examining the impact of candidate dominant and recessive mutations, as well as characteristic changes in microRNA expression, using novel cell-, zebrafish- and mouse-based assays developed by members of our group. Four projects will be pursued: Project 1: Functional annotation of human pancreatic cancer genes in a zebrafish system (Leach); Project 2: Discovery and evaluation of prioritized mutations in human pancreatic cancer (Kern); Project 3: The Hippo signaling pathway in pancreatic cancer (Maitra); and Project 4: Functional evaluation of microRNAs in pancreatic neoplasia (Mendell). These projects will be supported by three shared Cores: Core A: Cellular and Transgenic Phenotyping Core (Huso); Core B: Zebrafish Core (Parsons), and Core C: Administrative Core (Leach). The investigators pursuing these projects are all leaders in the field of pancreatic cancer research, and have an outstanding track record of synergistic interaction. The Program also leverages many already existing resources available at Johns Hopkins, including aspects of the NCI Gl SPORE grant, core resources provided by the Johns Hopkins Comprehensive Cancer Center, and the independently funded Pancreatic Cancer Genome Project. Together, these studies will dramatically accelerate the functional annotation of the pancreatic cancer genome, setting the stage for future therapeutic applications.