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 外分泌胰腺受伤后具有显着的再生能力，如急性胰腺炎所示， 和慢性胰腺炎的子集。腺泡 - 导向变质（ADM）对于外分泌的能力至关重要 胰腺再生或允许向前塑性状态（胰腺上皮内肿瘤或 Panin）。小鼠胰腺中致癌kras*（=突变kras）的表达会导致潘丁的形成 长期潜伏期的病变表明需要遗传和可能的表观遗传“第二次命中”。慢性的 胰腺炎被认为是人类胰腺导管腺癌（PDA）的强大危险因素。在 胰腺癌的小鼠模型，诱导急性或慢性胰腺炎会导致整个组织ADM 接下来是快速维修（我们将其设计为“自适应” ADM）。但是，在有致癌的情况下 Kras*，维修受损，ADM发展为Panin病变（我们将其指定为“致癌” ADM）。 目前，ADM形成以及ADM如何发展到Panin的基础机制 突变kras*的存在仍然未知。最近，我们的小组对鼠进行了基因表达分析 从发育中的胰腺，急性胰腺炎（ADM）和Panin表达致癌的导管细胞 KRASG12D，并将表达曲线与正常胰管细胞的表达曲线进行了比较，几乎导致 80个潜在的感兴趣基因。 PRRX1（配对相关的同源物1）是最差异的调节 在所有三个过程中的转录因子，其次是ETV5，ETS的转录家族成员 因素。基于引人注目的发布和初步数据，我们假设ETV5和PRRX1是 胰腺炎后分别参与ADM的主动性和维护。此外，我们 假设该调节允许随后通过致癌kras*进行转化，从而促进 向潘宁发展。该假设将通过以下相互关联的特定目的进行检验：（1） 确定胰腺损伤后ADM和Panin是否需要PRRX1； （2）阐明关系 在ADM功能调节中的ETV5和Sox9之间； （3）识别和评估的基因靶标 prrx1和ikras*（可诱导的突变kras）在“致癌” ADM（Panin）的发展中。这个目标 确定prrx1和ikras*的影响。我们的创新和综合研究将定义转录 ADM的调节并为胰腺炎和Panin治疗的新观点提供了基础。