Notch regulation of exocrine pancreatic precursors

在胚胎发育过程中调节胰腺外分泌分化的信号通路知之甚少。这些途径可能在几种人类疾病状态中发挥关键作用，包括慢性胰腺炎和胰腺导管腺癌。这项研究项目的长期目标是确定负责控制胰腺外分泌前体细胞的分子通路。初步研究表明，腺泡细胞分化的变化可能通过EGF和Notch信号通路之间的新的相互作用来调节。具体地说，已经证明转化生长因子-α改变了小鼠胰腺腺泡细胞的分化状态，重新激活了以胚胎样上皮扩张为特征的发育程序。转化生长因子-α对外分泌分化的影响似乎是通过激活Notch信号通路来实现的，Notch靶基因的反式激活和激活的Notch-1能够诱导类似的效应。此外，外分泌前体细胞中Notch伴侣RBP-J-kappa的选择性失活导致胰腺发育不良，无法产生成熟的腺泡和导管细胞类型。基于这些发现，我们认为Notch信号被反复地用来调节胰腺外分泌的正常发育，而Notch的异常激活可能是导致成人腺体发育可塑性和上皮细胞增殖的原因。为了验证这一假说，我们将追求以下特定目标：首先，研究Notch信号在正常胰腺发育过程中腺泡细胞分化中的作用。第二，研究Notch信号在成人胰腺转分化过程中的作用。最后，利用转基因和基于Cre/lox的方法，确定对小鼠外分泌胰腺中Notch信号的谱系特异性操纵的效果。为了完成这些研究，研究人员建立了一个由多学科科学家组成的团队，他们在胰腺细胞生物学、Notch信号转导和小鼠基因靶向领域拥有著名的专业知识。预计这些研究将为胰腺外分泌前体细胞的调控提供重要的新见解，并有可能为胰腺外分泌疾病提供新的治疗策略。

The signaling pathways regulating differentiation of the exocrine pancreas during embryonic development are poorly understood. These pathways may play a critical role in several human disease states, including chronic pancreatitis and pancreatic ductal adenocarcinoma. The long term goal of this research project is to identify molecular pathways responsible for controlling precursor cells in exocrine pancreas. Preliminary studies suggest that changes in acinar cell differentiation may be regulated by novel interactions between the EGF and Notch signaling pathways. Specifically, it has been demonstrated that TGF-alpha alters the differentiation status of acinar cells in mouse pancreas, reactivating a developmental program characterized by expansion of embryonic-like epithelium. The effects of TGF-alpha on exocrine differentiation appear to be mediated by activation of Notch signaling pathways, as evidenced by transactivation of Notch target genes and the ability of activated Notch-1 to induce similar effects. Moreover, selective inactivation of the Notch partner RBP-J-kappa in exocrine precursor cells results in pancreatic hypoplasia and a failure to generate mature acinar and ductal cell types. Based on these findings, we propose that Notch signaling is iteratively utilized to regulate normal development of the exocrine pancreas, and that abnormal Notch activation may be responsible for generating developmental plasticity and epithelial proliferation in the adult gland. To test this hypothesis, the following Specific Aims will be pursued: First, to investigate the role of Notch signaling in acinar cell differentiation during normal pancreatic development. Second, to examine the role of Notch signaling during transdifferentiation events in adult pancreas. Finally, to determine the effects of lineage-specific manipulation of Notch signaling in mouse exocrine pancreas, utilizing both transgenic and Cre/lox-based approaches. To accomplish these studies, the investigators have established a multidisciplinary team of scientists with noted expertise in the fields of pancreatic cell biology, Notch signaling, and mouse gene targeting. It is anticipated that these studies will provide important new insights regarding regulation of exocrine pancreatic precursor cells, and potentially generate new therapeutic strategies for diseases of the exocrine pancreas.