APPROACHES TO THE STUDY OF PANCREATIC REGENERATION

描述（改编自申请人的摘要）：本提案寻求 扩展了关于重组腺病毒基因的已有知识 转移到胰腺，并利用这些知识来研究两个基本的 胰腺生物学问题--胰腺再生与胰岛 形态发生 下面概述的实验是根据四个 这些假设是根据初步的 在PI实验室所做的工作，以及对 文学：1.）胰腺细胞中的瞬时基因表达 通过进一步研究， 所涉及的机制; 2.）宿主免疫调节是一种有前途的策略 用于建立长期基因表达; 3.）重组腺病毒可以 被工程化以表达参与胰腺生长的基因， 用于阐明再生生物学的探针; 4.）重组 腺病毒将有助于设计创新策略， 胰岛形态发生，并最终靶向胰岛进行基因治疗， vivo. 以下具体目标将在执行此赠款： 1.）目的研究重组腺病毒载体与重组腺病毒的相互作用， 免疫活性/免疫缺陷小鼠的胰腺; 2.）研究 重组腺病毒载体与胰腺的相互作用 免疫缺陷小鼠，并测试创新的方法，以延长病毒 转基因在转导到免疫活性小鼠中的胰腺中的表达; 3.） 研究生理扰动（链脲佐菌素，急性 胰腺炎，胰腺切除术）对胰腺定向基因稳定性的影响 4.目的：研究重组腺病毒介导的抗肿瘤作用。 胰腺生长基因regA和regB以及肝细胞生长因子 (HGF)试图刺激胰腺再生; 5.）以贝塔为目标 胰岛细胞通过促进长期基因表达， 观察转基因表达细胞从外周的转运。 的 从这些研究中获得的信息对于理解 胰腺再生和胰岛形态发生的生物学。 工作 还将使人们更深入地了解胰腺免疫学和 开发胰腺和胰岛定向基因的创新策略 疗法

DESCRIPTION (Adapted from Applicant's Abstract): This proposal seek to extend the knowledge already accumulated about recombinant adenoviral gene transfer to the pancreas, and to use this knowledge to study two fundamental problems of pancreatic biology-pancreatic regeneration and islet morphogenesis. The experiments outlined below were planned based on four overarching hypotheses which have been developed based on the preliminary work done in the laboratory of the PI, as well as extensive review of the literature: 1.) The transient gene expression seen in pancreatic cells transduced with recombinant adenoviruses can be overcome by further study of the mechanisms involved; 2.) Host immunomodulation is one promising strategy for establishing long-term gene expression; 3.) Recombinant adenoviruses can be engineered to express genes involved in pancreatic growth and used as probes to elucidate the biology of regeneration; 4.) Recombinant adenoviruses will be useful in designing innovative strategies to study islet morphogenesis, and ultimately target the islets for gene therapy in vivo. The following Specific Aims will be undertaken in the conduct of this grant: 1.) To study the interaction of recombinant adenoviral vectors with the pancreas of immunocompetent/immunodeficient mice; 2.) To study the interaction of recombinant adenoviral vectors with the pancreas of immunodeficient mice, and to test innovative approaches to prolonging viral transgene expression in pancreata transduced into immunocompetent mice; 3.) To study the effect of physiologic perturbations (streptozotocin, acute pancreatitis, pancreatic resection) on stability of pancreas directed gene transfer; 4.) To study the effect of recombinant adenoviruses encoding the pancreatic growth genes regA and regB as well as hepatocyte growth factor (HGF) in attempts to stimulate pancreatic regeneration; 5.) To target beta cells of the islets of Langerhans by promoting long-tern gene expression and observing transit of transgene expressing cells from the periphery. The information learned from these studies will be important in understanding the biology of pancreatic regeneration and islet morphogenesis. The work will also allow a deeper understanding of pancreatic immunology and the development of innovative strategies for pancreas and islet-directed gene therapy.