Networks for functional regulation of pancreatic acinar-ductal metaplasia and epithelial plasticity

胰腺腺泡导管化生和上皮可塑性的功能调节网络

• 批准号: 9977159
• 负责人: Anil K Rustgi
• 金额: $ 36.45万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977159
• 关键词: 3-Dimensional; Acinar Cell; Acute; Cells; Chronic; Data; Development; Duct (organ) structure; Ductal Epithelial Cell; Epigenetic Process; Epithelial; Epithelium; Exocrine pancreas; Expression Profiling; Family; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Health; Homeobox; Hour; Human; Impairment; Inflammation; Injury; Knock-out; Knockout Mice; Lesion; Maintenance; Mediating; Metaplasia; Mus; Natural regeneration; Oncogenic; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Injury; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pancreatitis; Population; Preneoplastic Conditions; Process; Publishing; Recovery; Regenerative response; Regulation; Research; Risk Factors; Role; Testing; Therapeutic; Tissues; Transcriptional Regulation; United States; acute pancreatitis; base; carcinogenesis; chronic pancreatitis; design; in vivo; innovation; insight; interest; member; mouse model; mutant; novel; novel strategies; novel therapeutics; pancreatic cancer model; premalignant; promoter; repaired; tissue regeneration; tissue repair; transcription factor

PROJECT SUMMARY The exocrine pancreas has a remarkable ability to regenerate after injury, as illustrated in acute pancreatitis, and subsets of chronic pancreatitis. Acinar-ductal metaplasia (ADM) is critical in the ability of the exocrine pancreas to regenerate or permit progression to a preneoplastic state (pancreatic intraepithelial neoplasia or PanIN). Expression of oncogenic Kras* (=mutant Kras) in the mouse pancreas leads to formation of PanIN lesions with long latency, indicating the need for genetic and possibly epigenetic “second hits”. Chronic pancreatitis is recognized as a strong risk factor for pancreatic ductal adenocarcinoma (PDA) in humans. In mouse models of pancreatic cancer, induction of either acute or chronic pancreatitis results in tissue-wide ADM that is followed by rapid repair (we designate this as “Adaptive” ADM). However, in the presence of oncogenic Kras*, repair is impaired and ADM progresses to PanIN lesions (we designate this as “Oncogenic” ADM). Currently, the mechanisms underlying the formation of ADM and how ADM progresses to PanIN in the presence of mutant Kras* remain unknown. Recently, our group performed gene expression analysis of murine ductal cells isolated from the developing pancreas, acute pancreatitis (ADM), and PanIN expressing oncogenic KrasG12D, and compared the expression profiles to that of normal pancreatic ductal cells, resulting in nearly 80 potential genes of interest. Prrx1 (paired-related homeobox 1) was the most differentially regulated transcription factor in all three processes, followed by Etv5, a member of the Ets family of transcriptional factors. Based upon compelling published and preliminary data, we hypothesize that Etv5 and Prrx1 are involved in the initiation and maintenance of ADM, respectively, following pancreatitis. Furthermore, we hypothesize that this regulation allows for subsequent transformation by oncogenic Kras*, thereby promoting progression to PanIN. This hypothesis will be tested through the following interrelated Specific Aims: (1) To determine if Prrx1 is required for ADM and PanIN following pancreatic injury; (2) To elucidate the relationship between Etv5 and Sox9 in the functional regulation of ADM; and (3) To identify and evaluate gene targets of Prrx1 and iKras* (inducible mutant Kras) in the development of “Oncogenic” ADM (to PanIN). This aim will identify effectors of Prrx1 and iKras*. Our innovative and integrated research will define the transcriptional regulation of ADM and provide a basis for new perspectives in the therapy of pancreatitis and PanIN.

项目概要 外分泌胰腺在受伤后具有显着的再生能力，如急性胰腺炎所示， 和慢性胰腺炎的亚型（ADM）对于外分泌的能力至关重要。 胰腺再生或进展至肿瘤前状态（胰腺上皮内瘤变或 PanIN)。致癌 Kras*（=突变体 Kras）在小鼠胰腺中的表达导致 PanIN 的形成。 病变潜伏期长，表明需要遗传和可能的表观遗传“第二次打击”。 胰腺炎被认为是人类胰腺导管腺癌（PDA）的强烈危险因素。 胰腺癌小鼠模型中，急性或慢性胰腺炎的诱导导致组织范围内的 ADM 然后是快速修复（我们将其称为“自适应”ADM）。 Kras*，修复受损，ADM 进展为 PanIN 病变（我们将其称为“致癌”ADM）。 目前，ADM 形成的机制以及 ADM 如何进展为 PanIN 最近，我们的小组对小鼠进行了基因表达分析。 从发育中的胰腺、急性胰腺炎 (ADM) 和表达致癌性的 PanIN 中分离出的导管细胞 KrasG12D，并将表达谱与正常胰腺导管细胞的表达谱进行比较，结果几乎 80 个潜在的感兴趣基因 Prrx1（配对相关同源盒 1）是差异调节程度最高的。 所有三个过程中都有转录因子，其次是 Etv5，它是转录 Ets 家族的成员 基于令人信服的已发布数据和初步数据，我们勇敢地说 Etv5 和 Prrx1 是。 分别参与胰腺炎后 ADM 的启动和维持。 进一步指出，这一规定允许致癌 Kras* 进行后续转化，从而促进 该假设进展为 PanIN。 该假设将通过以下相互关联的具体目标进行检验： (1) 到 确定胰腺损伤后 ADM 和 PanIN 是否需要 Prrx1；(2) 阐明两者之间的关系； Etv5 和 Sox9 在 ADM 功能调节中的作用；以及 (3) 识别和评估 ADM 的基因靶标 Prrx1 和 iKras*（诱导突变体 Kras）在“致癌”ADM 的开发中（PanIN）。 识别 Prrx1 和 iKras* 的效应子我们的创新和综合研究将定义转录。 ADM 的调控，为胰腺炎和 PanIN 的治疗提供新的视角基础。