Functional Annotation of the Pancreatic Cancer Genome

描述（由申请人提供）：在过去的十年中，我们对人类胰腺癌基因变化的理解取得了前所未有的进展。在项目研究人员的一系列重要贡献的带领下，胰腺癌的遗传和表观遗传基础已经慢慢被揭开，现在已经认识到30多个基因位点在这种疾病中发生突变，并且报道了更多数量的编码基因和非编码microrna的基因表达特征变化。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。本计划项目资助的中心目标是通过确定人类胰腺癌分子改变的功能意义，缩小遗传和功能数据之间的差距。该功能注释将通过检查候选显性和隐性突变的影响，以及microRNA表达的特征变化来实现，使用由我们小组成员开发的基于细胞、斑马鱼和小鼠的新型检测方法。项目1：斑马鱼系统中人类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Hippo信号通路（Maitra）；项目4：胰腺肿瘤中microrna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（Huso）；核心B：斑马鱼核心（帕森斯）和核心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，并且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 SPORE拨款、约翰霍普金斯大学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.