Gene Targets of Wnt Signaling in Pancreatic Cancer

描述(申请人提供)：应聘者：应聘者目前是 西雅图大学外科肿瘤科外科助理教授 辛辛那提大学。在开始这个教职员工职位之前 8/96，他是康奈尔大学医学中心的外科住院医生 然后是M.D.安德森癌症中心的外科肿瘤学研究员。洛伊博士 对学术外科肿瘤学有着坚定的承诺，他努力 作为一名护理者和一名研究人员，都表现出色。为此，他愿 在有组织、有指导的环境中继续他的基础研究培训 我们的目标是成为一名有效的、独立的调查员。 环境：本提案中概述的研究将由Dr。 分子遗传学系副教授乔安娜·格罗登 生物化学和微生物学，以及 霍华德·休斯医学院。格罗登博士是国际公认的 癌症遗传学和结肠腺瘤性息肉病研究专家 吉恩。格罗登博士和洛伊博士有着出色的工作关系 已经出版了同行评议的手稿。这将是 是促进洛伊博士成为一名 独立科学家。辛辛那提大学是一所富有的大学 工作、协作和学习的智力环境。数不胜数 医学院内部设有核心设施。研究：胰腺 癌症仍然是一种常见的疾病，在几乎所有病例中都是致命的。WNT 信号通路在多种恶性肿瘤中通过突变而被激活 结肠腺瘤性息肉病(APC)或β-连环蛋白基因。而APC还没有 以前被认为是胰腺中重要的肿瘤抑制因子，我们的 初步研究表明，Wnt信号在这些细胞中经常被激活 肿瘤。本应用的目的是鉴定Wnt的靶基因 胰腺癌的信号传导。中心假设是异常的Wnt 信号在胰腺癌的一个亚组中是活跃的，并有助于 特异性转录调控与胰管癌变 靶基因。核心假设将通过追求三个方面来检验 具体目标：1)确定与WNT相关的基因改变 胰腺癌组织中PαThway活化的研究 与已知的临床和病理预后因素的关系；2) 确定Wnt途径诱导的转录是否与缺失有关 胰腺癌细胞的生长控制；3)寻找Wnt的靶基因 胰腺癌细胞中的信号传导。我们的长期目标是了解 这些基因如何在胰腺癌的发生中起作用 它们可以被调节以用于治疗目的。

DESCRIPTION (provided by applicant): Candidate: The applicant is currently an Assistant Professor of Surgery in the Division of Surgical Oncology at the University of Cincinnati. Prior to starting this first faculty position in 8/96, he was a resident in surgery at Cornell University Medical Center and then a surgical oncology fellow at the M.D. Anderson Cancer Center. Dr. Lowy has a steadfast commitment to academic surgical oncology, and he strives to excel as both a caregiver and as a researcher. To this end, he would like to continue his basic research training in a structured, mentored environment w i t h the goal of becoming an effective, independent investigator. Environment: The research outlined in this proposal will be sponsored by Dr. Joanna Groden, an Associate Professor in the Department of Molecular Genetics, Biochemistry and Microbiology as well as an Assistant Investigator in the Howard Hughes Medical Institute. Dr. Groden is an internationally recognized expert in cancer genetics and in the study of the adenomatous polyposis coli gene. Dr. Groden and Dr. Lowy have an outstanding working relationship that has already resulted in publication of peer-reviewed manuscripts. This will be a tremendous asset in fostering Dr. Lowy's progress toward becoming an independent scientist. The University of Cincinnati is a rich and collegial intellectual environment in which to work, collaborate and study. Numerous core facilities are available within the Medical School. Research: Pancreatic cancer remains a common disease that is lethal in nearly all cases. The Wnt signaling pathway is activated in numerous malignancies by mutation of the adenomatous polyposis coli (APC) or beta-catenin genes. While APC has not previously been considered an important tumor suppressor in the pancreas, our preliminary work suggests that Wnt signaling is frequently activated in these tumors. The objective of this application is to identify target genes of Wnt signaling in pancreatic cancer. The central hypothesis is that aberrant Wnt signaling is active in a subset of pancreatic cancers and contributes to pancreatic duct carcinogenesis by transcriptional regulation of specific target genes. The central hypothesis will be tested by pursuing three specific aims: 1) To identify the genetic alterations associated with Wnt p a thway activation in pancreatic cancer in order to determine their relationship to known clinical and pathologic prognostic factors; 2) To determine whether Wnt pathway induced transcription is associated with loss of growth control in pancreatic cancer cells; 3) To identify target genes of Wnt signaling in pancreatic cancer cells. Our long-range goal is to understand how these genes contribute to pancreatic carcinogenesis with the hope that they can be modulated for therapeutic purposes.