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

项目总结 外分泌胰腺在损伤后具有显著的再生能力，如急性胰腺炎所示， 慢性胰腺炎的亚型。腺泡导管化生(ADM)是影响外分泌能力的关键因素。 胰腺再生或进展到癌前状态(胰腺上皮内瘤变或 Panin)。致癌基因Kras*(=突变型Kras)在小鼠胰腺中的表达导致泛宁的形成 潜伏期长的病变，表明需要遗传的，可能还有表观遗传的“二次点击”。慢性 胰腺炎被认为是人类胰腺导管腺癌(PDA)的重要危险因素。在……里面 小鼠胰腺癌模型，急性或慢性胰腺炎的诱导导致组织范围的ADM 然后是快速修复(我们将其指定为“自适应”ADM)。然而，在致癌基因存在的情况下 KRAS*，修复受损，ADM进展为PAIN皮损(我们将其称为“致癌”ADM)。 目前，ADM形成的机制以及ADM是如何发展为帕宁的 突变的Kras*的存在仍然未知。最近，我们课题组对小鼠的基因表达进行了分析 从发育中的胰腺分离的导管细胞、急性胰腺炎(ADM)和表达致癌的Panin KrasG12D，并将其与正常胰腺导管细胞的表达谱进行比较，结果显示 80个潜在的感兴趣基因。Prrx1(配对相关同源异型盒1)是差异调控最强的基因 转录因子在所有三个过程中，紧随其后的是ETS转录家族的成员ETV5。 各种因素。基于令人信服的已公布和初步数据，我们假设Etw5和Prrx1是 分别参与胰腺炎后ADM的启动和维持。此外，我们 假设这一规定允许致癌的Kras*随后的转化，从而促进 向帕宁进军。这一假设将通过以下相互关联的具体目标来检验：(1) 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 在ADM的功能调控中的作用；(3)确定和评估ADM的基因靶点 Prrx1和iKras*(可诱导突变体Kras)在发展“致癌”ADM(对Panin)中的作用。这一目标将 识别Prrx1和iKras*的效应器。我们的创新和综合研究将定义转录 对ADM的调控，为胰腺炎和泛宁的治疗提供了新的视角。

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.