The Novel Role of REST in the Development of Pancreatic Ductal Adenocarcinoma

REST 在胰腺导管腺癌发展中的新作用

• 批准号: 9753191
• 负责人: Julie Bray
• 金额: $ 2.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-12-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753191
• 关键词: Acinar Cell; Acinus organ component; Address; Adenovirus Vector; Benign; Binding; Binding Sites; Biological Assay; Breast Carcinoma; Cancer Etiology; Cancer cell line; Cell Line; Cells; Cessation of life; Clinic; Colon Carcinoma; DNA Binding; Data; Development; Diagnosis; Duct (organ) structure; Ductal; Ductal Epithelial Cell; Early Diagnosis; Enterobacteria phage P1 Cre recombinase; Epithelium; Firefly Luciferases; Gene Expression Profiling; Genes; Genetically Engineered Mouse; Goals; Human; Hyperplasia; In Vitro; Intervention; KRAS2 gene; Knock-out; Knockout Mice; Lead; Lesion; Luciferases; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Messenger RNA; Metaplasia; Modeling; Mus; Nature; Neoplasms; Neurons; Normal tissue morphology; Oncogenes; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatitis; Patients; Play; Predisposing Factor; Premalignant; Prevention; Preventive Intervention; Process; Promoter Regions; Proteins; Publishing; RE1-silencing transcription factor; Reporter Genes; Repression; Research Support; Rest; Role; Screening procedure; Survival Rate; Time; Tissues; Transcription Repressor/Corepressor; Transgenic Organisms; Tumor Suppressor Proteins; cell transformation; chromatin immunoprecipitation; comparative; experience; high risk; improved; in vivo; insight; lung Carcinoma; malignant breast neoplasm; mouse model; nerve stem cell; neurogenesis; new therapeutic target; novel; overexpression; pancreas development; pancreatic cancer cells; promoter; transcription factor; transcription factor REST; vector

Proposal Summary/Abstract While the 5-year survival rate of the most common cancers such as lung, colon, breast, and prostate cancer have improved over the last several decades, the 5-year survival rate of Pancreatic Ductal Adenocarcinoma (PDAC) have remained flat-lined at only 3%-7%. The aggressive nature of PDAC often subjugates the effects of current treatment options, and the lack of screening tools make early detection rare. The later stages of PDAC have been thoroughly characterized and studied, but the understanding of early pancreatic cancer development remains limited. The large body of published research supports the idea that pancreatic lesions originate from acinar cells that transdifferentiate into ductal-like cells- a process called acinar to ductal metaplasia (ADM). Broadly stated, this proposal aims to develop a better understanding of what drives ADM initiation and the role of ADM drivers in maintaining PDAC development. Our supporting in vitro data suggest that overexpression of transcriptional repressor REST in pancreatic acinar cells can sufficiently induce ADM transformation. While REST has been well characterized for its gene regulating role in neurogenesis, the functionality of REST in pancreatic cancer tissue remains largely unexplored. This proposal will use Chromatin Immunoprecipitation to identify direct binding targets of REST within pancreatic acinar cells, giving insight into the mechanism underlining the effects of REST in ADM progression. To determine if REST activity is necessary for ADM progression and PDAC development in vivo, this proposal will develop a novel REST mouse model with conditional knock-out of REST expression within acinar pancreatic cells. The effects of conditional REST knockout on ADM and early pre-cancerous lesions will be determined by inducing pancreatitis (PDAC pre- disposing factor) and quantifying ADM transformation. Furthermore, we will determine the effect of conditional REST knockout on impeding PDAC development and prolonging survival by crossing REST knockout mice with an established transgenic PDAC model. Our goal is to establish the role of REST activity in early and late PDAC to ultimately offer a new therapeutic target that serves as a prevention intervention for patients at high-risk of PDAC development and treatment intervention for PDAC patients.

提案摘要/摘要 而肺癌、结肠癌、乳腺癌和前列腺癌等最常见癌症的 5 年生存率 过去几十年来，胰腺导管腺癌的 5 年生存率有所提高 (PDAC) 一直保持在 3%-7% 的水平。 PDAC 的攻击性通常会抑制以下因素的影响： 目前的治疗方案和筛查工具的缺乏使得早期检测变得罕见。 PDAC的后期阶段 已被彻底表征和研究，但对早期胰腺癌发展的了解 仍然有限。大量已发表的研究支持胰腺病变起源于的观点 腺泡细胞转分化为导管样细胞，这一过程称为腺泡到导管化生 (ADM)。 概括地说，该提案旨在更好地理解 ADM 启动的驱动因素及其作用 ADM 驱动程序维护 PDAC 开发。我们的体外支持数据表明，过度表达 胰腺腺泡细胞中的转录抑制因子 REST 可以充分诱导 ADM 转化。尽管 REST 因其在神经发生中的基因调节作用而得到充分表征，REST 在神经发生中的功能 胰腺癌组织在很大程度上仍未被探索。该提案将使用染色质免疫沉淀来 识别胰腺腺泡细胞内 REST 的直接结合靶点，深入了解其机制 强调 REST 在 ADM 进展中的作用。确定 ADM 是否需要 REST 活动 体内进展和 PDAC 发育，该提案将开发一种新型 REST 小鼠模型 有条件地敲除腺泡胰腺细胞内的 REST 表达。条件休息的影响 敲除ADM和早期癌前病变将通过诱发胰腺炎（PDAC pre- 处置因素）并量化 ADM 转化。此外，我们将确定条件的效果 REST 敲除小鼠与 REST 敲除小鼠杂交可阻碍 PDAC 发育并延长生存期 已建立的转基因 PDAC 模型。我们的目标是确定 REST 活动在早期和晚期 PDAC 中的作用 最终提供一个新的治疗靶点，作为高危患者的预防干预措施 PDAC 的发展和 PDAC 患者的治疗干预。