Heparin-binding EGF in pancreatic disease

肝素结合 EGF 在胰腺疾病中的作用

• 批准号: 6861716
• 负责人: ANNA L MEANS
• 金额: $ 24.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861716
• 关键词: adenocarcinoma; biological signal transduction; cell population study; endocrine pharmacology; epidermal growth factor; fibrogenesis; fibrosis; gene expression; genetic manipulation; genetically modified animals; growth factor receptors; heparin; hormone regulation /control mechanism; hyperplasia; laboratory mouse; mixed tissue /cell culture; molecular pathology; pancreas; pancreas disorder; pancreas neoplasms; pathologic process

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.

描述（由申请人提供）：像许多上皮性肿瘤一样，胰腺腺癌在异常的纤维化微环境中发展。虽然这种环境被认为有助于肿瘤侵袭，但最近的实验表明，它也有助于上皮肿瘤的早期发展。我们已经建立了一种新的转基因小鼠模型，它发展为胰腺纤维化，随后生长到纤维化区域的增生性导管病变。这些病变被认为是胰腺腺癌的前兆。我们开发的转基因小鼠在正常表达的生长因子HB-EGF中有3倍的升高。因此，正常产生的生长因子的轻微不平衡能够诱导胰腺纤维化和导管增生。我们已经开始剖析这种疾病进展的分子机制，方法是从野生型和hb - egf过表达的胰腺中分离出不同的组织，并在离体培养中重组它们。将HB-EGF过表达的组织与正常的星状细胞（引起纤维化的细胞）重组，激活这些细胞，重现纤维形成的早期步骤。利用我们的体内小鼠模型结合离体共培养实验，我们建议通过降低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在纤维形成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和可溶性HB-EGF在疾病诱导中的作用，以及通过检查哪种细胞类型在诱导EGFR信号传导中直接响应HB-EGF，阐明HB-EGF、近分泌、旁分泌或自分泌产生的信号传导类型。拟议的实验将进一步加深我们对胰腺纤维形成的调控和细胞内过程的认识，以及纤维化与持续HB-EGF信号传导在上皮增生中的作用。