APPROACHES TO THE STUDY OF PANCREATIC REGENERATION

描述(改编自申请人摘要)：本提案旨在 扩展已积累的重组腺病毒基因知识 转移到胰腺，并利用这一知识学习两个基本知识 胰腺生物学问题--胰腺再生与胰岛 形态发生。下面概述的实验是在四个基础上计划的 在初步研究的基础上提出的总体假设 在国际和平研究所实验室所做的工作，以及对 文学：1.)胰腺细胞中的瞬时基因表达 通过进一步的研究可以克服重组腺病毒的转导 涉及的机制；2.)宿主免疫调节是一种很有前途的策略 用于建立长期基因表达；3)重组腺病毒可以 被改造成表达与胰腺生长有关的基因，并被用作 探索阐明再生的生物学；4)重组 腺病毒将有助于设计创新的策略来研究 胰岛形态发生，最终以胰岛为靶点进行基因治疗 活着。 在进行这笔赠款时，将实现以下具体目标： 1)目的：研究重组腺病毒载体与肿瘤细胞的相互作用。 免疫活性/免疫缺陷小鼠胰腺；为了研究 重组腺病毒载体与小鼠胰腺的相互作用 免疫缺陷小鼠，并测试延长病毒时间的创新方法 转免疫活性小鼠胰腺组织中的转基因表达； 研究生理扰动(链脲佐菌素、急性 胰腺炎、胰腺切除)对胰腺导向基因稳定性的影响 调任；4.)目的：研究重组腺病毒对小鼠胸腺功能的影响。 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；目标为测试版 通过促进Long-TERN基因的表达和胰岛细胞 观察外周转基因表达细胞的转运情况。这个 从这些研究中学到的信息将对理解 胰腺再生和胰岛形态发生的生物学。这项工作 还将使我们更深入地了解胰腺免疫学和 胰腺和胰岛导向基因的创新策略研究进展 心理治疗。

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.