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.

项目摘要 胰腺外分泌具有显著的损伤后再生能力，如急性胰腺炎， 和慢性胰腺炎的亚型。腺泡导管化生（ADM）是外分泌能力的关键， 胰腺再生或允许进展到癌前状态（胰腺上皮内瘤形成或 PanIN）。小鼠胰腺中致癌Kras*（=突变Kras）的表达导致PanIN的形成 潜伏期长的病变，表明需要遗传和可能表观遗传的“二次打击”。慢性 胰腺炎被认为是人类胰腺导管腺癌（PDA）的强危险因素。在 胰腺癌小鼠模型，急性或慢性胰腺炎的诱导导致组织范围的ADM 随后是快速修复（我们将其称为“自适应”ADM）。然而，在致癌的存在下， Kras*，修复受损，ADM进展为PanIN病变（我们将其命名为“致癌性”ADM）。 目前，ADM形成的机制以及ADM如何在胰腺癌中进展为PanIN尚不清楚。 突变型Kras* 的存在仍然未知。最近，我们的小组进行了小鼠的基因表达分析， 从发育中的胰腺、急性胰腺炎（ADM）和表达致癌基因PanIN的胰腺导管细胞分离， KrasG 12 D，并将其表达谱与正常胰腺导管细胞的表达谱进行比较，结果显示， 80个潜在的基因。Prrx 1（配对相关同源框1）是最差异调节 在所有这三个过程中，Ets转录因子，其次是Etv 5，转录家族的成员。 因素基于令人信服的已发表和初步数据，我们假设Etv 5和Prrx 1是 分别参与胰腺炎后ADM的启动和维持。而且我们 假设这种调节允许致癌Kras* 的后续转化，从而促进 升级到Panin。这一假设将通过以下相互关联的具体目标进行检验：（1） 确定胰腺损伤后ADM和PanIN是否需要Prrx 1;（2）阐明Prrx 1与ADM和PanIN之间的关系。 Etv 5和Sox 9在ADM功能调节中的作用;（3）筛选和评价Etv 5和Sox 9的基因靶点， Prrx 1和iKras*（诱导型突变Kras）在“致癌”ADM（至PanIN）发展中的作用。这一目标将 识别Prrx 1和iKras* 效应子。我们的创新和综合研究将定义转录 为胰腺炎和PanIN的治疗提供新的前景。