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

提案摘要/摘要 而最常见的癌症，如肺癌，结肠癌，乳腺癌和前列腺癌的5年生存率 在过去的几十年里，胰腺导管腺癌的5年生存率有所提高， （PDAC）仍然保持在3%-7%的水平。PDAC的侵略性通常会抑制 目前的治疗选择和缺乏筛查工具使得早期发现罕见。PDAC的后期阶段 已经被彻底的描述和研究，但是对早期胰腺癌发展的理解 仍然有限。大量已发表的研究支持胰腺病变起源于 腺泡细胞转分化为导管样细胞--一个称为腺泡到导管化生（ADM）的过程。 概括地说，这项建议旨在更好地理解是什么推动了ADM的启动和作用， ADM驱动因素在维护PDAC开发中的作用。我们的支持性体外数据表明， 胰腺腺泡细胞中的转录抑制因子REST可充分诱导ADM转化。而 REST在神经发生中的基因调节作用，REST在神经发生中的功能， 胰腺癌组织仍然大部分未被探索。该提案将使用染色质免疫沉淀法， 确定胰腺腺泡细胞内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。要确定REST活动是否是ADM所必需的， 进展和体内PDAC的发展，该提案将开发一种新的REST小鼠模型， 胰腺腺泡细胞内REST表达的条件性敲除。条件REST的影响 ADM和早期癌前病变的敲除将通过诱导胰腺炎（PDAC pre- 处理因素）和量化ADM转化。此外，我们将确定条件的效果 REST基因敲除对阻碍PDAC发展和延长生存期的作用，通过将REST基因敲除小鼠与 建立转基因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。 最终提供一种新的治疗靶点，作为高风险患者的预防干预， PDAC的发展和PDAC患者的治疗干预。

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.