Heparin-binding EGF in pancreatic disease

描述(申请人提供)：像许多上皮性肿瘤一样，胰腺癌在不正常的纤维化微环境中发展。虽然这种环境被认为是肿瘤侵袭的原因，但最近的实验表明，它也有助于上皮性肿瘤的早期发展。我们已经建立了一种新的转基因小鼠模型，该模型发展为胰腺纤维化，随后是生长到纤维化区的增生性导管病变。这些病变被认为是胰腺癌的先兆。我们开发的转基因小鼠的正常表达的生长因子HB-EGF增加了3倍。因此，正常产生的生长因子的轻微失衡会导致胰腺纤维化和导管增生。我们已经开始通过从野生型和HB-EGF过表达的胰腺组织中分离不同的组织，并在体外培养中重组它们，来剖析这种疾病进展的分子机制。将HB-EGF过度表达的组织与引起纤维化的正常星状细胞重组，激活这些细胞，重现纤维化形成的早期步骤。利用我们的体内小鼠模型和体外共培养实验，我们建议通过使用降低EGFR活性的转基因小鼠和使用EGFR及其下游效应物的药理抑制剂来阐明HB-EGF受体EGFR在纤维化和导管增生以及胰腺星状细胞激活中的作用。我们还将通过测试跨膜型和可溶性HB-EGF在疾病诱导中的作用以及通过检测哪种细胞类型在诱导EGFR信号中直接响应HB-EGF来阐明HB-EGF、旁分泌、旁分泌或自分泌产生的信号类型。拟议的实验将进一步加深我们对胰腺纤维化的调控和细胞内过程的了解，以及纤维化与持续的HB-EGF信号结合在上皮增生中所起的作用。

DESCRIPTION (provided by applicant): Like many epithelial tumors, pancreatic adenocarcinomas develop in an abnormal fibrotic microenvironment. While this environment is thought to contribute to tumor invasion, recent experiments have shown that it also contributes to early development of epithelial tumors. We have established a novel transgenic mouse model that develops pancreatic fibrosis followed by hyperplastic ductal lesions that grow into the fibrotic regions. These lesions are thought to be precursors to pancreatic adenocarcinoma. The transgenic mice we have developed have a 3-fold elevation in a normally expressed growth factor, HB-EGF. Thus, a slight imbalance in a normally produced growth factor is able to induce pancreatic fibrosis and ductal hyperplasia. We have begun to dissect the molecular mechanisms underlying this disease progression by isolating different tissues from wildtype and HB-EGF-overexpressing pancreata and recombining them in ex vivo culture. Recombining HB-EGF overexpressing tissue with normal stellate cells, the cells that give rise to fibrosis, activates these cells, reproducing early steps in fibrogenesis. Using our in vivo mouse model combined with ex vivo co-culture experiments, we propose to elucidate the role of the HB-EGF receptor, EGFR, in fibrogenesis and ductal hyperplasia and in the activation of pancreatic stellate cells by using genetically modified mice that have reduced EGFR activity and by using pharmacological inhibitors of EGFR and its downstream effectors. We will also elucidate the type of signaling produced by HB-EGF, juxtacrine, paracrine, or autocrine by testing the role of transmembrane and soluble HB-EGF in disease induction and by examining which cell type responds directly to HB-EGF in the induction of EGFR signaling. The proposed experiments will further our knowledge of the regulation and intracellular processes of pancreatic fibrogenesis and the role that fibrosis, combined with sustained HB-EGF signaling, has on epithelial hyperplasia.