Epigenetic regulation of pancreatic cancer

胰腺癌的表观遗传调控

基本信息

批准号：
8646377
负责人：
Matthias Hebrok
金额：
$ 32.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-03 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646377
关键词：
Ablation Acinar Cell Address Adult Benign Cancer Etiology Cells Cessation of life Chromatin Remodeling Factor Clinical Code Collaborations Cues Data Development Diagnosis Duct (organ) structure Ductal Early Diagnosis Enzymes Epigenetic Process Epithelium Gene Expression Gene Targeting Genes Goals Growth Human Intraepithelial Neoplasia Knowledge Lesion Longevity Malignant Neoplasms Malignant neoplasm of pancreas Mediating Medicine Metaplasia Molecular Molecular Analysis Morphology Mucinous Mus Neoplasms Neoplastic Cell Transformation Oncogenic Pancreas Pancreatic Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic duct Papillary Physiological Population Process Proteins Regulation Role Sampling Series Specimen Staging Stem cells Testing Therapeutic Intervention Transgenic Animals Transgenic Mice Transgenic Model United States Universities Utah base cell type chromatin remodeling combat human disease insight intraepithelial mouse model mutant neoplastic new therapeutic target novel novel diagnostics novel marker outcome forecast overexpression prevent progenitor public health relevance response tool tumor tumor initiation

项目摘要

Project Summary/Abstract Pancreatic adenocarcinoma (PDA) carries one of the most dismal prognoses in all of medicine and is currently the 4th leading cause of cancer death in the United States. Several subtypes of PDA have been identified that vary greatly with regard to their lethality. Preliminary studies presented in this proposal support the notion that diverse PDA subtypes form from distinct pancreas cell populations, including duct and acinar cells. Importantly, we have identified a specific gene coding for a chromatin remodeling enzyme that modulates the response to tumor-inducing cues in these different cell types. Elimination of the gene in duct cells of transgenic mice supports the development of morphological and molecular changes associated with the formation of the more benign PDA subtype. In contrast, the gene product is required for the development of the more aggressive form of PDA in acinar cells. Thus, we have identified a novel regulator of PDA subtype formation. We propose to test how the loss of the chromatin remodeler changes the differentiation state of pancreatic duct cells and makes them prone to develop the more benign subset of pancreatic cancer. Conversely, we present an experimental strategy to test how the loss of this gene prevents formation of the more aggressive form of PDA from acinar cells. We have already identified potential target genes for both the aggressive and more benign subtypes and will test whether manipulation of these factors initiates or prevents the early stages of benign and aggressive tumor formation. Finally, we are focusing on one particular target that we recently characterized to be essential for the development of the aggressive form. In this application we will test whether changes in gene expression of that factor can interfere with the development of the PDA subtypes. Throughout the proposal, we are using state of the art transgenic animals and molecular tools to address the questions outlined above. Furthermore, we have established close collaborations with clinical colleagues both at UCSF and at the University of Utah who will provide us with specimen of human cancer samples to test and verify that new factors identified in our mouse models have relevance to the human disease. It is our goal to identify both novel diagnostic markers that can be used for the early detection of the subsets of PDA as well as novel therapeutic targets that could be exploited to attack the cancer ones it has formed. These studies fulfill a critical gap as our knowledge about the formation and molecular mechanisms underlying the development of the more benign form of pancreatic cancer is limited. By understanding how the more benign cancer forms and how this differs from the formation of the aggressive form, we hope to gain critical insights into how one can manipulate the aggressive tumors to reduce it growth potential.

项目摘要/摘要胰腺腺癌（PDA）具有所有医学中最令人沮丧的预后之一，目前是美国癌症死亡的第四个主要原因。已经确定了几种PDA的亚型在其杀伤力方面差异很大。本提案中提出的初步研究支持来自不同胰腺细胞种群的不同PDA亚型，包括管道和腺泡细胞。重要的是，我们已经确定了编码调节染色质重塑酶的特定基因对这些不同细胞类型中肿瘤诱导线索的反应。消除管道中的基因转基因小鼠支持与形态学和分子变化的发展形成更良性的PDA亚型。相比之下，基因产物是需要开发的腺泡细胞中PDA的更具侵略性形式。因此，我们确定了PDA亚型的新型调节剂形成。我们建议测试染色质重塑的损失如何改变胰管的分化状态细胞，使它们容易发展胰腺癌的更良性子集。相反，我们在场一种实验策略，用于测试该基因的丢失如何阻止形成更具侵略性的形式来自腺泡细胞的PDA。我们已经确定了侵略性和更多的潜在靶基因良性亚型，并将测试操纵这些因素是启动还是阻止良性和侵略性肿瘤形成。最后，我们专注于我们最近的一个特定目标特征在于侵略性形式的发展至关重要。在此应用程序中，我们将测试该因子基因表达的变化是否会干扰PDA亚型的发展。在整个提案中，我们使用最先进的转基因动物和分子工具来解决上面概述的问题。此外，我们已经与临床同事建立了密切的合作在UCSF和犹他大学，他们将为我们提供人类癌症样本的标本进行测试和验证我们的小鼠模型中确定的新因素是否与人类疾病相关。这是我们的目标确定可用于早期检测PDA子集的新型诊断标记以及可以利用的新型治疗靶标可以攻击其形成的癌症。这些研究达到了关键的差距，因为我们对形成和分子机制的知识胰腺癌更良性形式的发展受到限制。通过了解更多良性癌的形式以及这与侵略性形式的形成如何不同，我们希望获得关键深入了解如何操纵侵袭性肿瘤以降低其生长潜力。